Journal of Antimicrobial Chemotherapy (2006) 57 384ndash410

doi101093jacdki473

Advance Access publication 31 January 2006

Fluconazole for the management of invasive candidiasiswhere do we stand after 15 years

C Charlier12 E Hart3 A Lefort1 P Ribaud4 F Dromer2 D W Denning5

and O Lortholary12

1Universite Paris V Service des Maladies Infectieuses et Tropicales Hopital Necker Enfants Malades

Paris France 2Unite de Mycologie Moleculaire CNR Mycologie et Antifongiques CNRS FRE 2849

Institut Pasteur Paris France 3Department of Infectious and Tropical Diseases North Manchester General

Hospital Dlaunays Road Manchester M8 9LR UK 4Service drsquoHematologie-Greffe de Moelle

Hopital Saint-Louis Paris France 5The University of Manchester Education and Research Centre

Wythenshawe Hospital Southmoor Road Manchester M23 9LT UK

Candidaspp are responsible formostof the fungal infections inhumansAvailable since1990 fluconazoleis well established as a leading drug in the setting of prevention and treatment of mucosal and invasivecandidiasis Fluconazole displays predictable pharmacokinetics and an excellent tolerance profile in allgroups including the elderly and children Fluconazole is a fungistatic drug against yeasts andlacks activity against moulds Candida krusei is intrinsically resistant to fluconazole and other speciesnotably Candida glabrata often manifest reduced susceptibility Emergence of azole-resistant strains aswell as discovery of new antifungal drugs (new triazoles and echinocandins) have raised important ques-tions about its use as a first line drug The aim of this review is to summarize themain available data on theposition of fluconazole in the prophylaxis or curative treatment of invasive Candida spp infectionsFluconazole is still a major drug for antifungal prophylaxis in the setting of transplantation (solid organand bone marrow) intensive care unit and in neutropenic patients Prophylactic fluconazole still has aplace in HIV-positive patients in viro-immunological failure with recurrent mucosal candidiasis Flucona-zole can be used in adult neutropenic patients with systemic candidiasis as long as the species identifiedisapriori susceptibleAmongnon-neutropenicpatientswithcandidaemia fluconazole isoneof the first linedrugs for susceptible speciesCases reports anduncontrolled studieshavealso reported its efficacy in thesetting of osteoarthritis endophthalmitismeningitis endocarditis and peritonitis causedbyCandida sppamongimmunocompetentadults Inpaediatrics fluconazole isawell toleratedandmajorprophylacticdrugfor high-risk neonates as well as an alternative treatment for neonatal candidiasis Importantly 15 yearsafter its introduction in the antifungal armamentarium fluconazole is still a first line treatment option inseveral cases of invasive candidiasis Its prophylactic use should however be limited to selected high-riskpatients to limit the risk of emergence of azole-resistant strains

KeywordsCandidaspp neutropenia intensive careunit bonemarrow transplantation solid organ transplantationsystemic candidiasis

Introduction

Fluconazole was discovered by Richardson et al12 working atPfizer in Sandwich UK in a programme initiated in 1978 Theoriginal patent covering its structure had been filed by Riley andcolleagues at ICI Pharmaceuticals who discontinued antifungalresearch prior to fluconazolersquos launch Fluconazole was identifiedbecause of its in vivo activity and only many years later were

in vitro systems found to measure in vitro activity Phase 2 studiescommenced in 1988 and were focused on Candida cryptococcaland coccidioidal infections initially using doses of 50 mg daily3ndash6

Prophylaxis studies in neutropenia followed The increasing needfor orally active azoles because of the AIDS epidemic andrespectable efficacy despite low doses of the drug led to rapidFoods and Drugs Administration and European licensures in 1990(httpwwwfdagovbbstopicsANSWERSANS00051html 21

Correspondence address Universite Paris V Infectious Diseases Department Necker Enfants Malades University Hospital 149 rue de Sevres75015 Paris France Tel +33-1-42-19-26-63 Fax +33-1-42-19-26-22 E-mail olivierlortholarynckaphpfr

384 The Author 2006 Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy All rights reserved

For Permissions please e-mail journalspermissionsoxfordjournalsorg

September 2005 date last accessed) Fears of severe idiosyncraticliver failure akin to ketoconazole effects did not materialize andlarger doses of fluconazole were explored for more seriously illpatients especially for those with cryptococcal and coccidioidalmeningitis and invasive candidiasis The last is the focus of thisreview

The aim of this article is to review the current prophylacticor curative use of fluconazole in the management of invasivecandidiasis 15 years after its introduction in theanti-infective armamentarium Probably in excess of 100 millionpatients have received fluconazole worldwide between 1990and 2005

Pharmacokinetics and pharmacodynamics

Mechanism of action

Fluconazole is a semi-synthetic azole designated an imidazole dueto the presence of three nitrogen atoms on the azole ring which isactive against numerous yeasts but not filamentous fungi It acts bythe inhibition of C-14 a demethylase which is required for ergo-sterol synthesis an essential building block of fungal cell mem-brane C-14 a demethylase is part of the fungal cytochrome P450complex and as such can also have an effect on thehuman cytochrome P450 complex leading to potential drug inter-actions and side effects Fluconazole is a fungistatic drug againstCandida spp7

Pharmacokinetics

Fluconazole is well absorbed with a bioavailability of over 80Peak levels are reached in 1ndash2 h in healthy fasting adults andgastrointestinal absorption is not influenced by the gastric pHIts volume of distribution is reported to be 07ndash10 Lkg and11 is protein bound8 The majority is excreted via the kidneys(60ndash75) with a further 8ndash10 being recoverable from the faecesIt is also removed by haemodialysis The half-life is 27ndash34 h inadult population allowing for once-a-day administration

The pharmacokinetics of fluconazole vary with age Neonateshave a 2- to 3-fold higher volume of distribution than adults(2 Lkg) that falls to 1 Lkg by 3 months of age9 The meanvolume of distribution is greater and more variable in prematureneonates It is therefore necessary to double the fluconazole dosefor neonates in order to achieve comparable plasma levels Becauseof reduced glomerular filtration and reduced activity of hepaticenzymes the half-life is increased in neonates compared withadults (55ndash90 h) It is thus recommended to administer the drugevery 72 h in neonates during the first 2 weeks of life and thenevery 48 h in weeks 2ndash4 of life Following this period daily dosingwould be appropriate1011

The diffusion in tissues and body fluids is excellent with CSFconcentrations reaching at least 70 of blood levels even in theabsence of inflamed meninges (see Table 1)8

A small study of four patients looking at the penetrationof fluconazole into brain tissue found that brain levels closelyparalleled plasma levels with a daily dose of 400 mg suggestingthat this dose may be appropriate for those with brain abscessescaused by susceptible yeasts12 A case report of acute cholecystitisdue to Candida albicans found higher biliary concentrationof fluconazole with oral dosing compared with intravenousdosing13 Fluconazole penetrates well into joint fluids for the

treatment of septic arthritis Fluconazole can also be administeredintraperitoneally for candidal peritonitis in patients on continuousambulatory peritoneal dialysis with good bioavailability (87) andplasma levels14 The ocular penetration is also good15 Indeedaqueous humour concentrations are reported to reach over 80of the serum concentration within the day following administrationof a single oral dose of 200 mg fluconazole16

Formulations

Different formulations are available for the treatment or prophy-laxis of systemic candidiasis tablets capsules oral solution andintravenous formulation The intravenous formulation is a simplesolution in water

Dosing

In adults (prophylaxis or treatment) A dose of 200ndash400 mgday isrecommended in prophylactic setting For the treatment of systemiccandidiasis a loading dose of 800 mgday is recommended on thefirst day followed by a 400 mgday dose

In children A wide range of doses has been used in childrenRecommended doses are of 3 mgkgday after the age of 1 yearNeonates with invasive candidiasis should receive 3ndash6 mgkg every72 h during the first 2 weeks of life every 48 h during 2ndash4 weeksof life and then once a day at the same dose1117

In pregnancy Owing to good bioavailability and volume of dis-tribution fluconazole is found in breast milk Fetal abnormalitieshave been reported after long-term usage among pregnantwomen18 Manufacturers recommend that fluconazole is to beavoided if breast feeding and that it should be used in pregnancyonly if the potential benefit justifies the possible risk to the fetus

In renal failure As fluconazole is mainly renally excreted somedose alterations are recommended for those with a decreased crea-tinine clearance see Table 2

Table 1 Diffusion of fluconazole in body tissues and fluids (http

wwwpfizercompfizerdownloaduspi_diflucanpdf 29 September

2005 date last accessed)

Tissue

Ratio of tissue fluconazole

concentrations to plasma

fluconazole concentrations

CSF 05ndash09

Saliva 1

Sputum 1

Blister fluid 1

Urine 10

Normal skin 10

Nails 1

Blister skin 2

Vaginal tissue 1

Vaginal fluid 04ndash07

Eye 08

Review

385

In other settings In a small review of 14 surgical patients hospi-talized in the intensive care unit (ICU) with fluconazole-susceptible deep mycoses enteral fluconazole was found to givesimilar levels in urine and exudates from the site of infection as didparenteral fluconazole Levels in patients with thermal burns varyconsiderably from normal to shorter half-lives possibly due to thegreater volume of distribution19 Patients on fluconazole prophy-laxis during bone marrow transplantation (BMT) who develophaemorrhagic cystitis secondary to chemotherapy excrete morefluconazole in their urine than those who do not20

Drug interactions

Owing to fluconazolersquos metabolism via the liver and the CYP450family of enzymes the potential exists for many drug interactionsTable 3 lists some of the more important drug interactions

Case reports also include an individual with raised carba-mazepine levels during concomitant fluconazole use presumedto be due to cytochrome P450 inhibition21 However decreasedfluconazole and other azole levels have also been reported infour patients receiving concomitant antiepileptic therapy leadingto antifungal failure2223 As a weak inhibitor of cytochrome P450-3A fluconazole at the standard dose does not inhibit clearance ofthe H-1 antagonist terfenadine Higher doses (gt200 mgday) arecontraindicated with terfenadine because of the risk of impairmentof the clearance of the drug and exposing the patients to severe sideeffects including QTc-interval prolongation24 (httpwwwpfizercompfizerdownloaduspi_diflucanpdf 29 September 2005 datelast accessed)

Side effects

Fluconazole displays an excellent profile of tolerance in the rangeof doses recommended in invasive candidiasis Side effects dooccur especially with doses gt400 mgday They have been reportedto occur more often in those with the human immunodeficiencyvirus (HIV)25 Common side effects include headache nausea andabdominal pain Raised transaminase serum levels may occur insome cases from 1 of cases in preventive use for BMT to 10 inpreventive use for patients with acute leukaemia and even 20 inthe setting of ICU26ndash28 Although generally mild elevation of livertransaminases can eventually lead to the stopping of fluconazolePatients with AIDS might be at higher risk for hepatotoxicity withfluconazole29 Rare cases of fulminant hepatitis have beenreported30 Hair loss which is reversible on stopping the drugand anorexia have also been reported3132

Table 2 Fluconazole dose reduction in case of renal failure (http

wwwpfizercompfizerdownloaduspi_diflucanpdf 29 September

2005 date last accessed)

Creatinine clearance Percentage of recommended dose

gt50 mLmin 100

11ndash50 mLmin 50

Haemodialysis patients 100 after each dialysis

Haemofiltration 200

Table 3 Major drugs interactions with fluconazole (21-4)

Drug Mechanismeffect Action

Ciclosporin increased ciclosporin AUC monitor ciclosporin levels may be enhanced

antifungal activity

Hydrochlorothiazide 40 increase in fluconazole levels

(D Denning unpublished data)

Glimepiride via CYP2C9 increased AUC with high doses

of fluconazole gt400 mg

dose reduction may be necessary

Losartan via CYP2C9 losartan accumulates consider an alternative antifungal monitor

blood pressure

Methadone via CYP3A4 increased AUC consider an alternative monitor for

increased narcotic effects

Midazolam increased AUC monitor for increased sedation

Phenytoin increased AUC monitor for phenytoin toxicity consider

using ketoconazole

Rifabutin via CYP3A4 increased AUC consider alternative rifamycin monitor

for rifabutin toxicity

Rifampicin via CYP3A4 accelerates fluconazole metabolism dose increase fluconazole by 25 may be necessary

Tacrolimus via CYP3A4 increased risk of interaction if doses of

fluconazole gt100 mgday

monitor tacrolimus levels reduction in

dose may be necessary

Warfarin via CYP2C9 doses of fluconazole gt100 mg reduced

warfarin metabolism

monitor INR as possible increase

Cyclophosphamide

and CYP450 associated

antineoplastic agents

via CYP3A4 and 2C9 doses of fluconazole

gt200 mg may accelerate

cyclophosphamide metabolism

no specific recommendation

CYP cytochrome P INR international normalized ratio

Review

386

Neurotoxicity can occur with very high doses above 1200 mgday33 Very unusually anaphylaxis and Stevens Johnson syndromehave been reported34

Safety and tolerability have been also clearly assessed inthe paediatric population mirroring the excellent profile oftolerance observed in adult population35 In 1999 Novelli andHolzel reviewed data from 562 children treated with fluconazole103 presented with treatment-related side effects including 77involving gastrointestinal tract disturbances and 12 involvingthe skin35

Monitoring of levels

There are no routine indications for measuring fluconazolelevels Patients with short bowel who require long-termtherapy may require confirmation of absorption Drug monitoringshould be performed among neonates (especially prematureinfants) with invasive candidiasis to ensure therapeutic plasmaconcentrations of fluconazole within a range between 4 and20 mgL Salivary concentrations are proportional to plasmalevels after 1 week and could potentially be used to monitorcompliance36

Pharmacodynamics

Dose-fractionation studies demonstrated that the pharmaco-dynamic parameter of fluconazole that best predicted outcomein experimental systemic candidiasis was the AUCMIC ratio37

However clinical response is also related to the immune status ofthe patient and presence of foreign materials or vegetations38

Activity of fluconazole against Candida species

It should be noted that breakpoints have been defined for the sus-ceptibility of Candida species to fluconazole using the M27NCCLS method39 Candida isolates are qualified as susceptibleif MIC values are pound8 mgL S-DD (susceptible dependent upondose) if at 16 or 32 mgL and resistant if Dagger64 mgL When con-sidering the relevance of these breakpoints they have been wellvalidated for the management of mucosal candidiasis in HIV-infected patients but much less for the treatment of systemic can-didiasis

Generally first isolates of Candida spp are susceptible to flu-conazole when they are first isolated from a patient who has notbeen treated with an azole with the exception of all Candida kruseiand occasional isolates of other species When examining the sus-ceptibility of Candida species currently isolated from blood cul-tures it indeed appears that Dagger95 of C albicans isolates remainsusceptible to fluconazole This is also the case for Candida tropi-calis and Candida parapsilosis (refs 40 41 Observatoire deslevures and F Dromer unpublished data) The worldwide per-centage of Candida glabrata susceptible to fluconazole accordingto geography ranges between 621 in Latin America and 809 inthe Asia-Pacific region42

The susceptibility data are much different in the populationsreceiving long-term fluconazole prophylaxis These data will bepresented later in the article

Fluconazole for prophylaxis of systemic candidiasisin transplanted patients

Solid organ transplants

Liver transplants Among solid organ transplantation liver trans-plantation has conveyed the highest risk of fungal infectionCandida species accounting for at least 60 of them4344

C albicans is the most frequently involved followed byC glabrata and C tropicalis The subsequent associated mortalityof these infections is high ranging between 30 and 1004345

Invasive candidiasis is strongly related to several conditionshaemodialysis or a creatinine level of Dagger2 mgdL fungal coloniza-tion ICU hospitalization exposure to gt3 antibiotics acute hepaticfailure surgical events (urgent surgery a long procedure gt11 hbiliary digestive anastomosis and the need for substantial intra-operative transfusions) and several post-operative events Theseinclude re-intervention haemodialysis early colonization (frompound2 days before to Dagger3 days after transplantation) retransplantationbiliary leaks infarcted tissue bacterial and cytomegalovirus andHHV-6 infections46ndash52 Enhanced immunosuppression with ster-oids OKT3 monoclonal antibody treatment of rejection as well asantimicrobial prophylaxis to prevent ascites infection may alsofacilitate the development of invasive candidiasis Thus subgroupspresenting a high risk of invasive candidiasis have been individu-alized and are the appropriate targets of fluconazole prophylaxisThe annual incidence of invasive candidiasis among liver trans-plant recipients has been estimated to range between 6 and 15 butis now decreasing due to significant technical developments sur-gical improvements and the wide use of fluconazole as fungalprophylaxis in this subset of high-risk patients Indeed Singhet al in a retrospective study documenting the evolving trendsin liver transplantation practices and their impact on fungal infec-tions observed a significant decline in the incidence of invasivecandidiasis Candida infections occurred in 9 of the patientsbetween 1990 and 1992 in 15 between 1993 and 1995 andin 17 of the patients from 1996 onwards44

Three randomized double-blind studies have shown the efficacyof fluconazole in the prevention of candidiasis in this setting (seeTable 4) In 1996 Lumbreras et al53 compared the efficacy ofnystatin (4 middot 106 U every 6 h n = 67) versus fluconazole (oral 100mgday n = 76) administered during the first 4 weeks after trans-plantation Fluconazole significantly reduced the rate of Candidasp colonization (7 versus 17) and proven superficial infection(10 versus 25) with a trend towards a reduction of invasivecandidiasis (2 versus 9) At that dose fluconazole was safe andwell tolerated without any interference with ciclosporin In 1999Winston et al46 studied fluconazole (oral 400 mgday n = 119)compared with placebo (n = 117) given for 10 weeks after trans-plantation Fluconazole significantly reduced the incidence of fun-gal colonization (34 versus 78) superficial infection (4versus 28) and invasive infection (6 versus 23) Of interestfluconazole also reduced the mortality associated with invasivefungal infection (2 versus 13) although global mortality ratewas not reduced among fluconazole-treated population (11versus 14) However significantly higher serum ciclosporinlevels were reported in the fluconazole-treated group In 2002Winston et al54 compared the efficacy of fluconazole (oral 400mgday n = 108) versus itraconazole (oral 200 mg twice a day n =104) given for the first 10 weeks after transplantation Both equallyreduced the rate of colonization (from first to last day of treatment)

Review

387

Table

4

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

inli

ver

tran

spla

nt

reci

pie

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Ref

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yd

esig

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en

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t

Nu

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ero

f

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ts

Pro

ven

Candida

sp

infe

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()

Su

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al

infe

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Inv

asiv

e

infe

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ns

Candida

sp

colo

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atio

n

atth

eE

OT

Dea

th

Win

sto

net

al

54

R

DB

PC

S

C

FL

C4

00

mg

day

po

ver

sus

itra

con

azo

le

20

0m

g1

2h

D0

toW

10

91

97

4

9

(P=

02

5)

1

2

3

7

30

25

8

12

Win

sto

net

al

46

R

DB

F

LC

40

0m

gd

ayD

0to

W1

01

08

9

4

6

34

11

PC

S

Cp

ov

ersu

sp

lace

bo

10

443

(Plt0001)28

(Plt0001)23

(Plt0001)

78

Plt0001)

14

at

W1

0

Lu

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rera

set

al

53

R

DB

v

s

tt

MC

FL

C1

00

mg

day

po

ver

sus

ny

stat

in

D0

toD

28

76

67

12

27

(P=0022)

10

25

(P=0034)

1

9

(P=

01

2)

7

17

(Plt0001)

13

13

at

D9

0

4middot

10

6U

day

To

rto

ran

oet

al

56

R

NB

F

LC

20

0m

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ayp

oD

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D2

83

80

24

vs

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sus

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ho

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15

00

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6h

37

3

ND

ND

32

N

D

Ku

nget

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57

HC

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10

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ura

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50

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ver

sus

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tmen

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ot

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72

ND

ND

8

ND

42

at

12

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nth

s

Dec

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ote

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and

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ized

Ret

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no

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pla

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oll

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Ww

eek

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ent

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done

Val

ues

giv

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face

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call

ysi

gnif

ican

t

Review

388

from 77 to 30 for fluconazole and from 67 to 25 for itracona-zole Rates of invasive candidiasis were similar to those describedin the authorrsquos former study Other studies have also looked tothe contribution of fluconazole in the prophylaxis of invasivecandidiasis in liver transplant recipients

Tortorano et al55 in 1995 observed a better prevention andclearance of C albicans colonization with fluconazole than withoral amphotericin B although clearance of Candida spp was notfound to be different because of fluconazole inefficiency on non-albicans species Finally Kung et al56 in a historical comparisonreported a higher survival rate among patients receiving flucona-zole as prophylaxis (n = 45 100 mgday) compared with untreatedpatients (n = 72) 75 versus 58 As highlighted by the recentlypublished Infectious Diseases Society of America (IDSA) guide-lines fluconazole-based prophylaxis is therefore recommendedamong high-risk liver transplant recipients (with Dagger2 previouslydefined risk factors) during the early post-operative period57

This practice has been shown to be efficient in decreasing theincidence of invasive candidiasis However a shift towards non-albicans Candida species in colonization or invasive infections hasoccurred during the past 10 years with a rise from 15 to 39 afterwidespread use of fluconazole49 This trend emphasizes that the useof fluconazole as prophylaxis should be strictly targeted to high-risk patients and not be generalized to all liver recipients

Kidney transplants Given the low incidence of severe Candida spinfections in this population and the lack of specific studies the useof fluconazole is not recommended in this setting in Europe andNorth America5859

Pancreas and pancreasndashkidney transplants Intra-abdominal andurinary tract infections are the most common sites of fungal infec-tions among pancreas and pancreasndashkidney transplant recipientsIn a retrospective survey of 445 consecutive pancreatic andpancreasndashkidney transplantations fungal intra-abdominal infec-tions occurred in 41445 (92) patients and were associatedwith three times higher risk of death60 87 of all invasive fungalinfections following pancreas transplantation are caused byCandida species61 Enteric drainage procedures living relativedonor as well as previous or simultaneous kidney transplantationare associated with a higher incidence of fungal infection60 Under-lying diabetes mellitus is a predisposing condition A consistentcharacteristic of pancreas-transplanted patients with candidiasis iscolonization of the urine with Candida species62 Benedetti et al60

observed that patients receiving fluconazole prophylaxis (n = 108400 mgday for 7 days) had lower rate of fungal infection than thosewho did not (n = 327) 6 versus 10 It should be noted thatrandomized comparative studies of antifungal prophylaxisin pancreas transplantation are lacking However data from theBenedetti study suggest that fluconazole might be administeredprophylactically in that setting especially in patients who experi-enced high-risk procedures or those colonized by Candida spp

Small bowel transplantation In a retrospective study of 29 patientswith small bowel transplantation Kusne et al63 reported 20 casesof invasive fungal infections 16 of them due to Candida specieswhich was involved in 9 of all positive blood cultures Althoughnever evaluated current recommendations advocate that flucona-zole might be administered in that setting57 The use of newbiological immunosuppressants such as almetuzumab whichis associated with severe T cell cytopenia and high risk of

opportunistic infections might convey higher risk of infectionand could justify the use of preventive fluconazole64

Heart lung and heartndashlung transplantation Aspergillus is themain fungal pathogen involved in that setting Taken its lack ofefficacy on moulds fluconazole as any prophylaxis targetingCandida sp is not relevant436066

Bone marrow transplantation

Invasive fungal infections are still a major cause of morbidity andmortality among recipients of bone marrow or peripheral stem celltransplantation Allogeneic BMT recipients are at special risk66 Inthe pre-engraftment phase (day 0ndashday 30) the two major identifiedrisk factors for invasive fungal infections are (i) prolonged neu-tropenia and (ii) breaks in the mucocutaneous barrier67 Themost prevalent fungal pathogens are yeasts especially Candidaspp and as neutropenia continues Aspergillus sp Post-engraft-ment from day 30 to day 100 is characterized by impaired cell-mediated immunity Susceptibility to fungal infections is thenrelated to factors suppressing the T lymphocyte immune responseexistence of graft-versus-host disease use of corticosteroids oranti-T lymphocyte antibodies and use of T-depleted graftsThis period is more likely associated with mould infections espe-cially with Aspergillus sp and also to some extent to chronicdisseminated candidiasis68 Two main randomized double-blindstudies have demonstrated the benefit of fluconazole amongBMT recipients (allogeneic + autologous) as shown in theTable 56970 At the dose of 400 mgday fluconazole was ableto significantly decrease the risk of superficial and invasive can-didal infections and the overall number of deaths related to fungaldisease Furthermore fluconazole was able to reduce the fungalcolonization at the endpoint of evaluation Slavin et al showed asignificant decrease of overall mortality at day 110 post-allogeneictransplantation after a 75 day regimen of fluconazole70 Confirma-tion and extension of this benefit was shown by Marr et al71 on thesame cohort with the survival benefit persisting after up to 8 yearsof follow-up Indeed administration of placebo was shown to be anindependent factor for poor survival

Fluconazole has also been compared with other antifungal drugsin allogeneic and autologous BMT (see Table 6) It has been shownto be as efficient as intravenous amphotericin B (02 mgkgday) forlowering Candida colonization and superficial and invasive fungalinfections in randomized non-blinded trials73 Three randomizednon-blinded studies have compared the efficacy of itraconazoleand fluconazole in bone marrow recipients with conflictingresults74ndash76 Annaloro et al74 did not observe any difference ininfection-related death invasive candidiasis or in the need forcurative doses of amphotericin B Winston et al75 observed sta-tistically more invasive fungal infections in the fluconazole groupthan in the itraconazole one (n = 138 25 versus 9) all of themrelated to non-albicans Candida species and moulds (Aspergillussp Fusarium sp and Rhizopus sp) However no difference insurvival could be detected Tolerance of itraconazole was lowerthan that of fluconazole Marr et al76 failed to show any superiorityof itraconazole in an intention-to-treat analysis whereas on-treat-ment analysis revealed a higher rate of invasive fungal infection inthe fluconazole group (mostly invasive mould infections) How-ever only one study has shown increased incidence of infectionsdue to Aspergillus species or other moulds in patients treated withfluconazole79 Therefore although with a spectrum of activity

Review

389

Table

5

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

pla

ceb

oo

rn

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eral

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rtal

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71

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00

mg

day

firs

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ayw

ith

PM

Nlt

50

0m

m3

15

2(1

8)

ND

ND

C3

9

C1

F8

55

ver

sus

pla

ceb

ou

nti

lD

+7

51

48

(17

)C20

(Plt0001)

14

C8

F6

(P=0001)

72

(P=

00

00

1)

Sla

vin

etal

70

R

DB

PC

S

C

FL

Cp

o4

00

mg

day

Fir

std

ayw

ith

PM

Nlt

50

0m

m3

15

2(1

8)

77

0

7

7

Clt1

F7

20

ver

sus

pla

ceb

ou

nti

lD

+7

51

48

(17

)86 (P

=0037)

7

(Plt0001)

18 (P

=0004)

13

C9

F4

35 (P

=0004)

Ala

ng

aden

etal

72

HC

FL

Cp

o1

00

or

2w

eek

sb

efo

re1

12

(28

)70

4

9

20

0m

gd

ay

ver

sus

no

trea

tmen

t

BM

Tu

nti

l

PM

Ngt

50

0m

m3

79

(40

)82

ND

10 (P

lt005)

ND

18

Go

od

man

etal

69

R

DB

PC

M

C

FL

Cp

o4

00

mg

day

ver

sus

pla

ceb

o

firs

td

ay

con

dit

ion

ing

reg

imen

17

9(8

6)

30

8

3

C2

F1

1

31

un

til

eng

raft

men

t

(PM

Ngt

10

3m

m3)

17

7(1

00

)67 (P

lt0001)

33 (P

lt0001)

16

C14

F2

(Plt0001)

6

26

Rr

andom

ized

Ret

rre

trosp

ecti

ve

DB

double

bli

ndP

Cp

lace

bo

contr

oll

edD

day

SC

sin

gle

centr

eM

Cm

ult

icen

tre

HC

his

tori

calc

om

par

ison

au

toa

uto

logo

us

bo

ne

mar

row

FL

Cf

luco

naz

ole

po

ora

lE

OT

en

do

ftr

eatm

ent

IFI

inv

asiv

efu

ng

alin

fect

ion

N

Dn

ot

do

ne

CCandida

sp

Ffi

lam

ento

us

fun

gi

PM

Np

oly

mo

rph

on

ucl

ear

cell

sB

MT

b

on

em

arro

wtr

ansp

lan

tati

on

V

alu

esg

iven

inb

old

face

are

stat

isti

call

ysi

gnif

ican

t

Review

390

Table

6

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

oth

eran

tifu

ng

als

inal

log

enei

can

dau

tolo

go

us

bo

ne

mar

row

tran

spla

nt

pat

ien

ts

Ref

eren

ceS

tud

yd

esig

nR

egim

enD

ura

tio

no

ftr

eatm

ent

Nu

mb

ero

f

pat

ien

ts

(au

to)

Su

per

fici

al

Candida

sp

infe

ctio

ns

Inv

asiv

e

fun

gal

infe

ctio

ns

Candida

sp

colo

niz

atio

n

atth

eE

OT

Dea

th

rela

ted

toIF

I

Ov

eral

l

dea

th

van

Bu

riket

al

79

R

DB

M

CF

LC

po

40

0m

gd

ay

ver

sus

mic

afu

ng

in

(50

mg

day

)

48

hb

efo

reco

nd

itio

nin

g

reg

imen

un

til

eng

raft

men

t

45

7(2

01

)

42

5(2

03

)

ND

24

C

04

F2

16

C

09

F1

7

34

52

lt1

lt1

6

4

Mar

ret

al

76

R

NB

S

CF

LC

po

or

iv

40

0m

gd

ayv

ersu

s

itra

con

azo

le

75

mg

kg

po

20

0m

gd

ay

con

dit

ion

ing

reg

imen

toD

-12

0(n

=1

87

)

D-0

toD

-12

0(n

=1

02

)

14

8

15

1

ND

19

C

3

F1

6

18

C

3

F

15

ND

7

8

31

39

Win

sto

net

al

75

R

NB

M

CF

LC

po

or

iv4

00

mg

day

ver

sus

itra

con

azo

le

iv2

00

mg

day

or

po

25

mg

kg

day

middot3d

ay

D-1

toD

-10

0

afte

rB

MT

68

72

3

4

25

9

(P=001)

ND

ND

42

45

Ko

het

al

22

7R

N

B

SC

FL

Cp

o2

00

mg

day

ver

sus

amp

ho

teri

cin

B

iv0

2m

gk

gd

ay

24

hb

efo

reco

nd

itio

nin

g

reg

imen

un

til

eng

raft

men

t

(PM

Ngt

50

0m

m3gt

3d

ays)

10

0(2

6)

86

(20

)

1

5

12

13

ND

6

7

22

30

Wo

lffet

al

73

R

NB

M

CF

LC

po

40

0m

gd

ay

ver

sus

amp

ho

teri

cin

B

iv0

2m

gk

gd

ay

D-1

pre

con

dit

ion

ing

reg

imen

un

til

eng

raft

men

t

(PM

Ngt

50

0m

m3)

19

6(1

42

)

15

9(1

10

)

ND

26

2

27

43

3

1

12

12

An

nal

oro

etal

74

R

NB

S

CF

LC

po

30

0m

gd

ay

ver

sus

FL

Cp

o

50

mg

day

ver

sus

itra

con

azo

le4

00

mg

day

D-1

pre

con

dit

ion

ing

reg

imen

un

til

eng

raft

men

t

(PM

Ngt

50

0m

m3)

28

30

31

ND

4

3

13

ND

no

dif

fere

nce

ND

Glu

ckm

anet

al

22

8R

N

B

SC

FL

Cp

oi

v

10

0m

gd

ay

ver

sus

ket

oco

naz

ole

40

0m

gd

ay

Dndash

8to

D+

90

afte

rB

MT

30

29

3

11

10

7

47

41

ND

ND

Rra

ndom

ized

D

Bdouble

bli

nd

NB

not

bli

nd

PC

pla

cebo

contr

oll

ed

SC

si

ngle

centr

eM

Cm

ult

icen

tre

FL

Cfl

uco

naz

ole

poora

liv

in

trav

eno

us

EO

Ten

do

ftr

eatm

ent

ND

n

ot

do

ne

CCandida

sp

F

fila

men

tous

fungi

PM

N

poly

morp

honucl

ear

cell

sB

MT

bone

mar

row

tran

spla

nta

tion

D

day

V

alues

giv

enin

bold

face

are

stat

isti

call

ysi

gnif

ican

t

Review

391

limited to yeasts fluconazole has been widely adopted as an effec-tive and safe therapy Its use is now recommended from the day ofhaematopoietic stem cell transplantation until engraftment inguidelines for prevention of opportunistic infections among allo-geneic bone marrow recipients67 The optimal dose of fluconazolein that setting is not clearly determined The posology of 400 mgday is recommended by the IDSA However lower doses have beenshown to be similarly effective in reducing the risk of invasiveinfections and candidal colonization7176 MacMillan et al77 in alarge cohort of 253 patients demonstrated similar efficiency of highand low dosages of fluconazole (200 and 400 mgday) on the rate offungal colonization and infection No increase of reduced suscep-tibility in isolates of Candida was seen at the low doses Theadoption of fluconazole as prophylactic regimen in BMT has raisedconcern about a shift of colonization towards azole-resistant strainsof Candida sp Indeed Marr et al78 observed that out of 585patients undergoing BMT with prophylactic fluconazole 44were colonized with Candida sp during the procedure half ofthem with a species other than C albicans However no increasein invasive candidiasis or in deaths related to non-albicans Candidainfections could be observed Very recently van Burik et al79 in alarge randomized double-blind multicentre study on 882 patientsobserved superior efficacy of the echinocandin micafungin (50 mgday) over fluconazole (400 mgday) on the prevention of invasivefungal infection among bone marrow recipients 80 of successversus 73 Further costndashbenefit studies are required to determinewhether micafungin could be an alternative to fluconazole in thatsetting particularly as fluconazole is now generic

Fluconazole for prophylaxis of Candida infections in

neutropenic patients

Neutropenic patients with haematological malignancies are at highrisk for developing invasive and superficial mycoses However allof them do not share the same risk of fungal infection

Prolonged deep neutropenia as observed in intensiveinduction or salvage regimens for acute leukaemia use of corti-costeroids and exposure to high-dose cytosine arabinoside or tomonoclonal antibodies (anti-CD52) are deeply immunosuppress-ing conditions facilitating the emergence of invasive fungalinfections80

Studies versus placebo Seven studies have shown the efficacy offluconazole in the setting of fungal prophylaxis among neutropenicpatients (excluding BMT) including five randomized double-blind placebo-controlled trials81ndash87 Indeed fluconazole hasbeen shown to significantly reduce Candida species colonizationsuperficial infections invasive proven candidal infections as wellas fungal-related mortality A broad range of doses were used inthese studies ranging from 50 to 400 mgday However no benefiton overall mortality has been observed (see Table 7)

Comparative studies Fluconazole has also been compared withother antifungal agents (see Table 8) When compared with oralpolyenes it was at least equivalent in terms of prevention of super-ficial infection except in the study by Rozenberg et al suggestingthat amphotericin B (400 mg middot 4day) might more efficientlyreduce superficial candidal colonization88ndash98 Egger et al88 alsosuggested that fluconazole might reduce the need for curativeamphotericin B among neutropenic patients but taken the absence

of consensus about the use of amphotericin B in the case of per-sistent fever these results are of low clinical pertinence Flucona-zole has an excellent tolerance profile in that population withsimilar efficiency and fewer side effects than intravenous polyeneprophylaxis98

Optimal dose is not clearly defined in neutropenic patientsDosages ranging from 100 to 400 mgday were used with appar-ently the same efficacy Low doses of 50 mgday prevent super-ficial candidiasis but not invasive disease Oral administration wasapparently as efficient as the intravenous one although this pointhad never been extensively studied in appropriate comparativestudies especially as more recent studies allowed either route ofadministration

Recently two meta-analyses reviewed the data extracted fromall major studies on fluconazole prophylaxis in neutropenicpatients with or without BMT99100 Comparators were fungal-related deaths superficial and invasive candidal infections useof parenteral antifungal therapy and infection and colonizationwith fluconazole-resistant species In 2000 Kanda et al reviewed16 controlled studies involving 3734 patients99 Superficial infec-tions were clearly reduced by the use of fluconazole (combined OR023 95 CI 017ndash031) In trials involving neutropenic patientswithout BMT the benefit of fluconazole on invasive infectionsappeared only in studies in which the incidence of fungal infectionwas gt15 with a combined OR at 023 (95CI 015ndash036) Therewas also no difference in the incidence rate of invasive aspergillosisbetween control and study groups Colonization by C krusei wasmore frequent in fluconazole-treated patients (OR 201 95 CI13ndash312) Colonization by C glabrata was more frequent amongpatients with low-dose (50ndash200 mgday) regimen (OR 204 95CI 118ndash353) However there was also no difference between testand control groups in the incidence rate of invasive proven infec-tions with C krusei C glabrata or Aspergillus sp Fungal-relatedmortality was not reduced in fluconazole-treated patients In 2002Bow et al100 similarly reviewed 38 trials including 14 involvingfluconazole (4062 patients with malignant disease and severe neu-tropenia) Fluconazole regimen was associated with benefit onsuperficial and invasive fungal infections and also on fungal infec-tion-related mortality (weighted OR 053 95 CI 034ndash083)Overall mortality was not reduced and no excess of invasiveaspergillosis could be evidenced One negative issue wassubsequently identified in a retrospective study including 3002patients Viscoli et al found that absorbable antifungalprophyl axis in neutropenic patients was associated with anincreased rate of bacteraemia with an estimated OR of 142(95 CI 107ndash188)101

There is no clear international recommendation about the use offluconazole or other antifungal drugs in the non-BMT profoundlyneutropenic setting The IDSA 2002 guidelines for the use ofantimicrobial agents in neutropenic patients with cancer indicatethat lsquoroutine use of fluconazole or itraconazole for all cases ofneutropenia is not recommended However in certain circum-stances in which the frequency of systemic infection due to Calbicans is high and the frequency of systemic infection due toother Candida species and Aspergillus species is low some physi-cians may elect to administer antifungal prophylaxis (D-II)102 InGerman guidelines fluconazole prophylaxis (400 mgday) amongpatients undergoing conventional chemotherapy is a grade C-Irecommendation (poor evidence)103 French guidelines on thecare of invasive candidiasis in adults were recently updatedThe use of fluconazole prophylaxis (400 mgday) is a high

Review

392

Table

7

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

pla

ceb

oo

rn

otr

eatm

ent

inn

eutr

op

enic

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

n

atth

eE

OT

Dea

th

Lav

erd

iere

etal

81

R

DB

PC

M

C

FL

C4

00

mg

day

po

ver

sus

pla

ceb

o

wit

hin

72

h

po

st-i

nit

iati

on

of

chem

oth

erap

y

un

til

PM

N

gt5

00

mm

3

13

5(6

0B

MT

)

13

1(5

8B

MT

)

ND

ND

3

17

Plt0001

31

75

ND

Ro

tste

inet

al

84

R

DB

F

LC

40

0m

gd

ayw

ith

in7

2h

14

1(6

2B

MT

)N

D7

3

015ndash023

ND

PC

M

Cp

ov

ersu

sp

lace

bo

po

st-i

nit

iati

on

of

chem

oth

erap

yu

nti

l

PM

Ngt

50

0m

m3

13

3(5

8B

MT

)18

(P=002)

16

(P=00001)

039ndash030

fungalindex

colonization

(Plt00001)

Ker

net

al

86

R

DB

SC

FL

C4

00

mg

day

po

ver

sus

no

trea

tmen

t

36

32

ND

ND

6

6

ND

no

dif

fere

nce

Sch

affn

eret

al

87

R

DB

PC

S

C

FL

C4

00

mg

day

po

iv

ver

sus

pla

ceb

o

adm

issi

on

un

til

sust

ain

edP

MN

gt5

00

mm

3

75

76

ND

1

12

(P

=0

01

8)

8

C0

F8

9

C5

F4

8

36

(Plt00001)

6

7

Yam

acet

al

85

R

NB

SC

FL

C4

00

mg

day

po

ver

sus

no

D0

chem

oth

erap

y

un

til

PM

N

41

29

ND

ND

9

31

(Plt005)

ND

ND

trea

tmen

tgt

2middot

10

3m

m3

Ch

and

rase

kar

83

R

DB

PC

S

C

FL

C4

00

mg

day

po

ver

sus

pla

ceb

o

D0

chem

oth

erap

yo

r

con

dit

ion

ing

or

reg

imen

un

til

D+

7af

ter

PM

Ngt

10

3m

l

23

(11

BM

T)

24

(11

BM

T)

ND

34

79

(P=

00

00

2)

10

C

0

F

10

5

C5

F0

ND

17

13

Win

sto

n8

2R

D

B

PC

M

C

FL

Cp

o4

00

mg

day

po

iv

ver

sus

pla

ceb

o

D0

chem

oth

erap

y

un

til

PM

Ngt

10

3m

l

12

4

13

2

9

21

(P=

00

2)

6

15

(Plt

00

1)

4

C1

F3

8

C4

5

F

35

29

68

(P=

00

01

)

21

18

R

rand

om

ized

D

B

do

uble

bli

nd

N

B

no

tb

lin

d

PC

p

lace

bo

con

troll

ed

SC

si

ng

lece

ntr

eM

C

mult

icen

tre

FL

C

flu

conaz

ole

p

o

ora

liv

in

trav

eno

us

EO

T

end

of

trea

tmen

tN

D

no

td

on

eC

Candida

sp

F

fila

men

tou

sfu

ng

iP

MN

p

oly

mo

rph

on

ucl

ear

cell

sB

MT

b

on

em

arro

wtr

ansp

lan

tati

on

D

d

ay

Val

ues

giv

enin

bo

ldfa

cear

est

atis

tica

lly

sign

ific

ant

Review

393

Table

8

Co

mp

arat

ive

stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

oth

eran

tifu

ng

als

inn

eutr

op

enic

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

nat

the

EO

TD

eath

Morg

enst

ern

etal

89

R

SB

MC

FL

C1

00

mg

day

po

ver

sus

itra

con

azo

le

25

mg

kg

twic

e

ad

ayp

o

beg

inn

ing

con

dit

ion

ing

reg

imen

un

til

PM

N

gt1

03m

m3gt

1w

eek

22

7

(12

0B

MT

)

21

8

(11

0B

MT

)

ND

5

2

3

C1

F2

1

C1

ND

4

1

Eg

ger

etal

88

R

NB

SC

FL

C4

00

mg

day

ivp

ov

ersu

sn

yst

atin

24middot

10

6U

middot3d

ayp

o

fro

mh

osp

ital

izat

ion

in

iso

lati

on

un

itu

nti

l

end

of

neu

tro

pen

ia

43

(14

BM

T)

46

(19

BM

T)

2

4

0

0

2

4

ND

ND

Bo

dey

etal

98

R

NB

SC

FL

C4

00

mg

day

po

ver

sus

AM

B

05

mg

kgmiddot3

wee

kiv

fro

mD

0ch

emo

ther

apy

un

til

PM

Ngt

10

3m

m3

41

36

4

8

0

0

4

8

18

15

15

9

Ell

iset

al

90

R

DB

SC

FL

Cp

o2

00

mg

day

ver

sus

clo

trim

azo

le

(10

mg

qid

)+

my

cost

atin

50

00

00

IUq

id

adm

issi

on

un

til

PM

Ngt

10

3m

m3

42

(10

BM

T)

48

(13

BM

T)

95

35

(Plt

00

1)

2

13

5

21

ND

19

35

(Plt004)

Men

ich

etti

R

NB

F

LC

15

0m

gd

ayp

oD

-3to

D-1

bef

ore

42

03

5

2

15

N

D1

0

etal

93

MC

ver

sus

AM

B5

00

mg

middot4d

ayp

o

chem

oth

erap

yu

nti

l

PM

Ngt

10

3m

m3

40

05

3

2

1

0

Nin

aneet

al

92

R

NB

MC

chil

dre

n

FL

Cp

o3

mg

kg

day

ver

sus

ny

stat

inp

o

50

00

0U

kg

qid

or

AM

B

25

mg

kg

qid

po

48

hw

ith

inin

itia

tio

n

of

chem

oth

erap

y

un

til

PM

Ngt

10

3m

m3

24

5

25

7

2

8

(P=0002)

1

6

(P=0004)

1

C0

5

F0

5

2

C2

no

dif

fere

nce

inre

du

ctio

n

and

con

tro

lo

f

colo

niz

atio

n

ND

Ak

iyam

a

etal

94

R

NB

SC

FL

C2

00

mg

day

po

ver

sus

AM

B8

00

mg

middot3d

ayp

o

D0

chem

oth

erap

y

un

til

PM

Ngt

50

0m

m3

71

59

ND

ND

1

3

2

9

ND

Ph

ilp

ott

-Ho

war

d

etal

91

R

NB

MC

FL

C5

0m

gd

ayp

ov

ersu

s

AM

B2

gd

ayp

oo

r

ny

stat

in4middot

10

6U

day

bef

ore

chem

oth

erap

y

un

til

PM

Ngt

10

3m

m3

or

4w

eek

s

26

9

26

7

4

12

(P=0001)

2

9

(Plt0001)

2

C1

F1

4

C3

5

F

05

sim

ilar

ND

Meu

nie

ret

al

95

R

NB

SC

FL

Cp

o2

00

mg

day

ver

sus

AM

Bp

o4

30

mg

day

D-2

neu

tro

pen

ia

un

til

PM

Ngt

10

3m

m3

30

(9B

MT

)

29

(9B

MT

)

7

13

0

3

14

C

7

F

7

17

C

10

F7

ND

17

21

Roze

nber

g-A

rska

etal

96

R

NB

SC

FL

C5

0m

gd

ayp

ov

ersu

s

AM

B4

00

mgmiddot4

day

po

D0

neu

tro

pen

ia

un

til

PM

Ngt

50

0m

m3

25

25

ND

0 4

4

C0

F4

4

C4

F0

52

16

ND

Bra

mm

eret

al

97

C

NB

F

LC

50

mg

day

NR

12

62

7

MC

po

ver

sus

ora

l

po

lyen

es

12

24

5

(su

spec

ted

fun

gal

infe

ctio

ns)

ND

ND

ND

ND

Rr

and

om

ized

DB

do

uble

bli

nd

NB

no

tbli

nd

SB

sin

gle

bli

nd

SC

sin

gle

cen

tre

MC

mult

icen

tre

FL

Cf

luco

naz

ole

po

ora

liv

in

trav

eno

us

EO

Te

nd

oftr

eatm

ent

ND

no

tdo

ne

CC

andida

sp

Ff

ilam

ento

us

fun

gi

PM

N

po

lym

orp

ho

nu

clea

rce

lls

BM

T

bo

ne

mar

row

tran

spla

nta

tio

n

D

day

q

id

fou

rti

mes

ad

ay

Val

ues

giv

enin

bo

ldfa

cear

est

atis

tica

lly

sign

ific

ant

Review

394

grade recommendation (A-I) among allogeneic bone marrowrecipients but not in the setting of autologous BMT or acuteleukaemia (httpwwwsrlforgDataDocumentsHTMLO2_refenticls_OA-recommendations20040513asp date last accessed26 December 2005) Thus in the light of the previously describedmeta-analysis fluconazole might be appropriate in neutropenicpatients with a high risk of fungal infection ie those with longduration of neutropenia prolonged corticosteroid therapy butprobably other drugs will be better choices

Fluconazole as prophylaxis for systemic

candidiasis in ICU adults

The extent of the problem There is an increasing incidence of bothbacterial and fungal sepsis occurring in ICU patients A USstudy found that the absolute number of deaths due to invasivemycoses rose from 1557 in 1980 to 6534 in 1997104 Althoughmuch of this increase was associated with fungal infections relatedto HIV there were also marked increases in deaths due to can-didiasis aspergillosis and other mycoses in the non-HIV popula-tion A UK study looking at the outcome of candidaemia infectionsreported 187 episodes of candidaemia per 100 000 finished con-sultant episodes Of them 454 occurred in an ICU setting andC albicans was isolated in 65 of cases105 A Swiss study foundthat two-thirds of episodes of candidaemia occurred in ICU or onsurgical wards with invasive candidiasis occurring 5ndash10 timesmore frequently in an ICU setting than on other wards106

Strikingly in spite of all therapeutic innovations in the field ofantifungal therapy the crude and attributable mortality of nosoco-mial fungaemias have not decreased over the past 15 years(38)107

How are patients at risk of invasive candidiasis identified Thediagnosis of invasive candidiasis may be difficult due to the highfrequency of colonization especially in patients who are on broadspectrum antibiotics A prospective study of non-neutropenicpatients in whom Candida species were isolated found that diges-tive and respiratory samples and the isolation of non-albicansspecies were risk factors for invasive candidiasis108 Additionallythe most significant risk factors for invasive candidaemia identifiedin a surgical ICU in those who had undergone surgery were priorsurgery acute renal failure receipt of total parenteral nutrition andthe presence of a central venous catheter109 This study also foundthat administration of an antifungal agent was associated withdecreased risk for invasive candidal infection For critically illsurgical patients Pittet et al110 proposed a Candida colonizationindex based on the ratio between the number of colonized sites andthe number of sites tested Although its use in hospital practice iscomplex expensive and time-consuming this index was highlypredictive of invasive candidiasis indeed a threshold of 05 ormore correctly identified the infected patients an average of 6days before the documented candidiasis An alternative approachhas been considered using both anti-Candida antibody and antigentitres111 A high concordance between the two has been observedfor patients with invasive candidal disease compared with patientswho were only colonized with Candida Sensitivity and specificityreached 100 and 833 respectively when the two tests werecombined112

Studies that have been done A recent paper has highlighted theimportance of appropriate trial design of antifungal prophylaxisand the need for appropriate assessment of risk factors to identify

those patients who are at higher risk113 Fluconazole has previouslybeen assessed as a prophylactic agent in ITU settings with contra-dictory results

Concerns over a shift inCandida isolates that are less susceptibleor resistant to fluconazole may be balanced against the justificationof using it in appropriately identified high-risk patients114

For Three prospective randomized placebo-controlled trials haveemphasized the efficacy of fluconazole in that setting (see Table 9)In one study 260 critically ill surgical patients staying in ICU forgt3 days mainly pre-hepatic transplantation patients were ran-domly assigned to either placebo or 400 mg of fluconazole perday The risk of fungal infection was reduced by 55 in the flu-conazole group compared with the control group who experienced15 of invasive infections115 In a small study of 43 surgicalpatients with recurrent gastrointestinal leaks or perforations theuse of fluconazole prophylaxis resulted in decreased isolation ofCandida in surveillance cultures and in a decrease in candidalperitonitis 4 versus 35 with a decrease in global invasivecandidiasis (9 versus 35)116 A slightly different approachwas used in a study of 204 critically ill patients in surgical andmedical ICU where fluconazole was used as part of a selectivedigestive decontamination regimen28 These patients appear tomore closely represent a typical group of ICU patients InvasiveCandida infections occurred less frequently in 8 of the flucona-zole group compared with 20 of the placebo group and no shifttowards non-albicans species was observed

Several reviews of historical cohorts have provided similarresults A recent retrospective review in a surgical ICU comparingthe use of fluconazole prophylaxis versus a historical cohort foundthat prophylaxis decreased the incidence of candidaemia and didnot find an increase in non-albicans species117 No reduction ofmortality with fluconazole was observed Secondary Candidainfections in high-risk patients with trauma occurred in 962(145) patients who did not receive fluconazole prophylaxiscompared with 3145 (2) of a historical cohort who did118

In another randomized prospective study of bacterial septicshock fluconazole had a measurable positive impact on survivalalthough no fungal infection was diagnosed This unclear benefi-cial effect might be related to fluconazolersquos observed ability toenhance the bactericidal activity of neutrophils or to prevent Can-dida spp infection which was not diagnosed by standard bloodcultures which are known to be relatively insensitive119120

Against One group of patients at increased risk of invasivecandidiasis includes those who have undergone recent liver trans-plantation In a previously cited prospective study of 35 post-liver-transplantation patients patients with C albicans infectionswere less likely to have received antifungal prophylaxis thanthose with non-albicans Candida infections (136 versus 50P = 004) Non-albicans Candida infections and prior antifungalprophylaxis correlated with poorer outcome49 A further studylooked at 125 critically ill patients who received either fluconazoleprophylaxis or placebo during their entire stay in ICU121 Therewere no significant differences in the incidence of candidal infec-tions nor any difference in the mortality or length of stay on ICU Inthe study performed by Pelz et al115 among pre-liver-transplanta-tion patients no benefit of fluconazole on survival could be noticedalthough a clear reduction of fungal infection was observed

There are however concerns that the use of prophylacticfluconazole in critical care patients favours the emergence of

Review

395

Table

4

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

inli

ver

tran

spla

nt

reci

pie

nts

Ref

eren

ceS

tud

yd

esig

nR

egim

en

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

()

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

n

atth

eE

OT

Dea

th

Win

sto

net

al

54

R

DB

PC

S

C

FL

C4

00

mg

day

po

ver

sus

itra

con

azo

le

20

0m

g1

2h

D0

toW

10

91

97

4

9

(P=

02

5)

1

2

3

7

30

25

8

12

Win

sto

net

al

46

R

DB

F

LC

40

0m

gd

ayD

0to

W1

01

08

9

4

6

34

11

PC

S

Cp

ov

ersu

sp

lace

bo

10

443

(Plt0001)28

(Plt0001)23

(Plt0001)

78

Plt0001)

14

at

W1

0

Lu

mb

rera

set

al

53

R

DB

v

s

tt

MC

FL

C1

00

mg

day

po

ver

sus

ny

stat

in

D0

toD

28

76

67

12

27

(P=0022)

10

25

(P=0034)

1

9

(P=

01

2)

7

17

(Plt0001)

13

13

at

D9

0

4middot

10

6U

day

To

rto

ran

oet

al

56

R

NB

F

LC

20

0m

gd

ayp

oD

0to

D2

83

80

24

vs

tt

SC

ver

sus

amp

ho

teri

cin

B

po

15

00

mg

6h

37

3

ND

ND

32

N

D

Ku

nget

al

57

HC

S

CF

LC

10

0m

gd

ayd

ura

tio

n4

50

35

ver

sus

no

trea

tmen

tn

ot

pre

cise

72

ND

ND

8

ND

42

at

12

mo

nth

s

Dec

ruy

enae

reR

etr

SC

FL

C2

00

mg

day

+D

0to

dis

char

ge

45

2

etal

22

6am

ph

ote

rici

nB

po

in

hig

h-r

isk

pat

ien

ts

ver

sus

amp

ho

teri

cin

Bp

oin

low

-ris

k

pat

ien

ts

fro

mIC

U

30

ND

ND

0

ND

ND

Rr

and

om

ized

Ret

rre

tro

spec

tiv

eD

Bd

ou

ble

bli

nd

NB

no

tbli

nd

PC

pla

ceb

oco

ntr

oll

edD

day

Ww

eek

vs

ttv

ersu

str

eatm

ent

SC

sin

gle

cen

tre

MC

mult

icen

tre

HC

his

tori

calc

om

par

isonF

LC

flu

conaz

ole

po

ora

lE

OT

en

dof

trea

tmen

tN

D

not

done

Val

ues

giv

enin

bold

face

are

stat

isti

call

ysi

gnif

ican

t

Review

388

from 77 to 30 for fluconazole and from 67 to 25 for itracona-zole Rates of invasive candidiasis were similar to those describedin the authorrsquos former study Other studies have also looked tothe contribution of fluconazole in the prophylaxis of invasivecandidiasis in liver transplant recipients

Tortorano et al55 in 1995 observed a better prevention andclearance of C albicans colonization with fluconazole than withoral amphotericin B although clearance of Candida spp was notfound to be different because of fluconazole inefficiency on non-albicans species Finally Kung et al56 in a historical comparisonreported a higher survival rate among patients receiving flucona-zole as prophylaxis (n = 45 100 mgday) compared with untreatedpatients (n = 72) 75 versus 58 As highlighted by the recentlypublished Infectious Diseases Society of America (IDSA) guide-lines fluconazole-based prophylaxis is therefore recommendedamong high-risk liver transplant recipients (with Dagger2 previouslydefined risk factors) during the early post-operative period57

This practice has been shown to be efficient in decreasing theincidence of invasive candidiasis However a shift towards non-albicans Candida species in colonization or invasive infections hasoccurred during the past 10 years with a rise from 15 to 39 afterwidespread use of fluconazole49 This trend emphasizes that the useof fluconazole as prophylaxis should be strictly targeted to high-risk patients and not be generalized to all liver recipients

Kidney transplants Given the low incidence of severe Candida spinfections in this population and the lack of specific studies the useof fluconazole is not recommended in this setting in Europe andNorth America5859

Pancreas and pancreasndashkidney transplants Intra-abdominal andurinary tract infections are the most common sites of fungal infec-tions among pancreas and pancreasndashkidney transplant recipientsIn a retrospective survey of 445 consecutive pancreatic andpancreasndashkidney transplantations fungal intra-abdominal infec-tions occurred in 41445 (92) patients and were associatedwith three times higher risk of death60 87 of all invasive fungalinfections following pancreas transplantation are caused byCandida species61 Enteric drainage procedures living relativedonor as well as previous or simultaneous kidney transplantationare associated with a higher incidence of fungal infection60 Under-lying diabetes mellitus is a predisposing condition A consistentcharacteristic of pancreas-transplanted patients with candidiasis iscolonization of the urine with Candida species62 Benedetti et al60

observed that patients receiving fluconazole prophylaxis (n = 108400 mgday for 7 days) had lower rate of fungal infection than thosewho did not (n = 327) 6 versus 10 It should be noted thatrandomized comparative studies of antifungal prophylaxisin pancreas transplantation are lacking However data from theBenedetti study suggest that fluconazole might be administeredprophylactically in that setting especially in patients who experi-enced high-risk procedures or those colonized by Candida spp

Small bowel transplantation In a retrospective study of 29 patientswith small bowel transplantation Kusne et al63 reported 20 casesof invasive fungal infections 16 of them due to Candida specieswhich was involved in 9 of all positive blood cultures Althoughnever evaluated current recommendations advocate that flucona-zole might be administered in that setting57 The use of newbiological immunosuppressants such as almetuzumab whichis associated with severe T cell cytopenia and high risk of

opportunistic infections might convey higher risk of infectionand could justify the use of preventive fluconazole64

Heart lung and heartndashlung transplantation Aspergillus is themain fungal pathogen involved in that setting Taken its lack ofefficacy on moulds fluconazole as any prophylaxis targetingCandida sp is not relevant436066

Bone marrow transplantation

Invasive fungal infections are still a major cause of morbidity andmortality among recipients of bone marrow or peripheral stem celltransplantation Allogeneic BMT recipients are at special risk66 Inthe pre-engraftment phase (day 0ndashday 30) the two major identifiedrisk factors for invasive fungal infections are (i) prolonged neu-tropenia and (ii) breaks in the mucocutaneous barrier67 Themost prevalent fungal pathogens are yeasts especially Candidaspp and as neutropenia continues Aspergillus sp Post-engraft-ment from day 30 to day 100 is characterized by impaired cell-mediated immunity Susceptibility to fungal infections is thenrelated to factors suppressing the T lymphocyte immune responseexistence of graft-versus-host disease use of corticosteroids oranti-T lymphocyte antibodies and use of T-depleted graftsThis period is more likely associated with mould infections espe-cially with Aspergillus sp and also to some extent to chronicdisseminated candidiasis68 Two main randomized double-blindstudies have demonstrated the benefit of fluconazole amongBMT recipients (allogeneic + autologous) as shown in theTable 56970 At the dose of 400 mgday fluconazole was ableto significantly decrease the risk of superficial and invasive can-didal infections and the overall number of deaths related to fungaldisease Furthermore fluconazole was able to reduce the fungalcolonization at the endpoint of evaluation Slavin et al showed asignificant decrease of overall mortality at day 110 post-allogeneictransplantation after a 75 day regimen of fluconazole70 Confirma-tion and extension of this benefit was shown by Marr et al71 on thesame cohort with the survival benefit persisting after up to 8 yearsof follow-up Indeed administration of placebo was shown to be anindependent factor for poor survival

Fluconazole has also been compared with other antifungal drugsin allogeneic and autologous BMT (see Table 6) It has been shownto be as efficient as intravenous amphotericin B (02 mgkgday) forlowering Candida colonization and superficial and invasive fungalinfections in randomized non-blinded trials73 Three randomizednon-blinded studies have compared the efficacy of itraconazoleand fluconazole in bone marrow recipients with conflictingresults74ndash76 Annaloro et al74 did not observe any difference ininfection-related death invasive candidiasis or in the need forcurative doses of amphotericin B Winston et al75 observed sta-tistically more invasive fungal infections in the fluconazole groupthan in the itraconazole one (n = 138 25 versus 9) all of themrelated to non-albicans Candida species and moulds (Aspergillussp Fusarium sp and Rhizopus sp) However no difference insurvival could be detected Tolerance of itraconazole was lowerthan that of fluconazole Marr et al76 failed to show any superiorityof itraconazole in an intention-to-treat analysis whereas on-treat-ment analysis revealed a higher rate of invasive fungal infection inthe fluconazole group (mostly invasive mould infections) How-ever only one study has shown increased incidence of infectionsdue to Aspergillus species or other moulds in patients treated withfluconazole79 Therefore although with a spectrum of activity

Review

389

Table

5

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

pla

ceb

oo

rn

otr

eatm

ent

inal

log

enei

can

dau

tolo

go

us

bo

ne

mar

row

tran

spla

nt

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts(a

uto

)

Candida

sp

colo

niz

atio

nat

the

EO

T

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Dea

th

rela

ted

toIF

I

Ov

eral

l

mo

rtal

ity

Mar

ret

al

71

R

DB

PC

S

C

FL

Cp

o4

00

mg

day

firs

td

ayw

ith

PM

Nlt

50

0m

m3

15

2(1

8)

ND

ND

C3

9

C1

F8

55

ver

sus

pla

ceb

ou

nti

lD

+7

51

48

(17

)C20

(Plt0001)

14

C8

F6

(P=0001)

72

(P=

00

00

1)

Sla

vin

etal

70

R

DB

PC

S

C

FL

Cp

o4

00

mg

day

Fir

std

ayw

ith

PM

Nlt

50

0m

m3

15

2(1

8)

77

0

7

7

Clt1

F7

20

ver

sus

pla

ceb

ou

nti

lD

+7

51

48

(17

)86 (P

=0037)

7

(Plt0001)

18 (P

=0004)

13

C9

F4

35 (P

=0004)

Ala

ng

aden

etal

72

HC

FL

Cp

o1

00

or

2w

eek

sb

efo

re1

12

(28

)70

4

9

20

0m

gd

ay

ver

sus

no

trea

tmen

t

BM

Tu

nti

l

PM

Ngt

50

0m

m3

79

(40

)82

ND

10 (P

lt005)

ND

18

Go

od

man

etal

69

R

DB

PC

M

C

FL

Cp

o4

00

mg

day

ver

sus

pla

ceb

o

firs

td

ay

con

dit

ion

ing

reg

imen

17

9(8

6)

30

8

3

C2

F1

1

31

un

til

eng

raft

men

t

(PM

Ngt

10

3m

m3)

17

7(1

00

)67 (P

lt0001)

33 (P

lt0001)

16

C14

F2

(Plt0001)

6

26

Rr

andom

ized

Ret

rre

trosp

ecti

ve

DB

double

bli

ndP

Cp

lace

bo

contr

oll

edD

day

SC

sin

gle

centr

eM

Cm

ult

icen

tre

HC

his

tori

calc

om

par

ison

au

toa

uto

logo

us

bo

ne

mar

row

FL

Cf

luco

naz

ole

po

ora

lE

OT

en

do

ftr

eatm

ent

IFI

inv

asiv

efu

ng

alin

fect

ion

N

Dn

ot

do

ne

CCandida

sp

Ffi

lam

ento

us

fun

gi

PM

Np

oly

mo

rph

on

ucl

ear

cell

sB

MT

b

on

em

arro

wtr

ansp

lan

tati

on

V

alu

esg

iven

inb

old

face

are

stat

isti

call

ysi

gnif

ican

t

Review

390

Table

6

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

oth

eran

tifu

ng

als

inal

log

enei

can

dau

tolo

go

us

bo

ne

mar

row

tran

spla

nt

pat

ien

ts

Ref

eren

ceS

tud

yd

esig

nR

egim

enD

ura

tio

no

ftr

eatm

ent

Nu

mb

ero

f

pat

ien

ts

(au

to)

Su

per

fici

al

Candida

sp

infe

ctio

ns

Inv

asiv

e

fun

gal

infe

ctio

ns

Candida

sp

colo

niz

atio

n

atth

eE

OT

Dea

th

rela

ted

toIF

I

Ov

eral

l

dea

th

van

Bu

riket

al

79

R

DB

M

CF

LC

po

40

0m

gd

ay

ver

sus

mic

afu

ng

in

(50

mg

day

)

48

hb

efo

reco

nd

itio

nin

g

reg

imen

un

til

eng

raft

men

t

45

7(2

01

)

42

5(2

03

)

ND

24

C

04

F2

16

C

09

F1

7

34

52

lt1

lt1

6

4

Mar

ret

al

76

R

NB

S

CF

LC

po

or

iv

40

0m

gd

ayv

ersu

s

itra

con

azo

le

75

mg

kg

po

20

0m

gd

ay

con

dit

ion

ing

reg

imen

toD

-12

0(n

=1

87

)

D-0

toD

-12

0(n

=1

02

)

14

8

15

1

ND

19

C

3

F1

6

18

C

3

F

15

ND

7

8

31

39

Win

sto

net

al

75

R

NB

M

CF

LC

po

or

iv4

00

mg

day

ver

sus

itra

con

azo

le

iv2

00

mg

day

or

po

25

mg

kg

day

middot3d

ay

D-1

toD

-10

0

afte

rB

MT

68

72

3

4

25

9

(P=001)

ND

ND

42

45

Ko

het

al

22

7R

N

B

SC

FL

Cp

o2

00

mg

day

ver

sus

amp

ho

teri

cin

B

iv0

2m

gk

gd

ay

24

hb

efo

reco

nd

itio

nin

g

reg

imen

un

til

eng

raft

men

t

(PM

Ngt

50

0m

m3gt

3d

ays)

10

0(2

6)

86

(20

)

1

5

12

13

ND

6

7

22

30

Wo

lffet

al

73

R

NB

M

CF

LC

po

40

0m

gd

ay

ver

sus

amp

ho

teri

cin

B

iv0

2m

gk

gd

ay

D-1

pre

con

dit

ion

ing

reg

imen

un

til

eng

raft

men

t

(PM

Ngt

50

0m

m3)

19

6(1

42

)

15

9(1

10

)

ND

26

2

27

43

3

1

12

12

An

nal

oro

etal

74

R

NB

S

CF

LC

po

30

0m

gd

ay

ver

sus

FL

Cp

o

50

mg

day

ver

sus

itra

con

azo

le4

00

mg

day

D-1

pre

con

dit

ion

ing

reg

imen

un

til

eng

raft

men

t

(PM

Ngt

50

0m

m3)

28

30

31

ND

4

3

13

ND

no

dif

fere

nce

ND

Glu

ckm

anet

al

22

8R

N

B

SC

FL

Cp

oi

v

10

0m

gd

ay

ver

sus

ket

oco

naz

ole

40

0m

gd

ay

Dndash

8to

D+

90

afte

rB

MT

30

29

3

11

10

7

47

41

ND

ND

Rra

ndom

ized

D

Bdouble

bli

nd

NB

not

bli

nd

PC

pla

cebo

contr

oll

ed

SC

si

ngle

centr

eM

Cm

ult

icen

tre

FL

Cfl

uco

naz

ole

poora

liv

in

trav

eno

us

EO

Ten

do

ftr

eatm

ent

ND

n

ot

do

ne

CCandida

sp

F

fila

men

tous

fungi

PM

N

poly

morp

honucl

ear

cell

sB

MT

bone

mar

row

tran

spla

nta

tion

D

day

V

alues

giv

enin

bold

face

are

stat

isti

call

ysi

gnif

ican

t

Review

391

limited to yeasts fluconazole has been widely adopted as an effec-tive and safe therapy Its use is now recommended from the day ofhaematopoietic stem cell transplantation until engraftment inguidelines for prevention of opportunistic infections among allo-geneic bone marrow recipients67 The optimal dose of fluconazolein that setting is not clearly determined The posology of 400 mgday is recommended by the IDSA However lower doses have beenshown to be similarly effective in reducing the risk of invasiveinfections and candidal colonization7176 MacMillan et al77 in alarge cohort of 253 patients demonstrated similar efficiency of highand low dosages of fluconazole (200 and 400 mgday) on the rate offungal colonization and infection No increase of reduced suscep-tibility in isolates of Candida was seen at the low doses Theadoption of fluconazole as prophylactic regimen in BMT has raisedconcern about a shift of colonization towards azole-resistant strainsof Candida sp Indeed Marr et al78 observed that out of 585patients undergoing BMT with prophylactic fluconazole 44were colonized with Candida sp during the procedure half ofthem with a species other than C albicans However no increasein invasive candidiasis or in deaths related to non-albicans Candidainfections could be observed Very recently van Burik et al79 in alarge randomized double-blind multicentre study on 882 patientsobserved superior efficacy of the echinocandin micafungin (50 mgday) over fluconazole (400 mgday) on the prevention of invasivefungal infection among bone marrow recipients 80 of successversus 73 Further costndashbenefit studies are required to determinewhether micafungin could be an alternative to fluconazole in thatsetting particularly as fluconazole is now generic

Fluconazole for prophylaxis of Candida infections in

neutropenic patients

Neutropenic patients with haematological malignancies are at highrisk for developing invasive and superficial mycoses However allof them do not share the same risk of fungal infection

Prolonged deep neutropenia as observed in intensiveinduction or salvage regimens for acute leukaemia use of corti-costeroids and exposure to high-dose cytosine arabinoside or tomonoclonal antibodies (anti-CD52) are deeply immunosuppress-ing conditions facilitating the emergence of invasive fungalinfections80

Studies versus placebo Seven studies have shown the efficacy offluconazole in the setting of fungal prophylaxis among neutropenicpatients (excluding BMT) including five randomized double-blind placebo-controlled trials81ndash87 Indeed fluconazole hasbeen shown to significantly reduce Candida species colonizationsuperficial infections invasive proven candidal infections as wellas fungal-related mortality A broad range of doses were used inthese studies ranging from 50 to 400 mgday However no benefiton overall mortality has been observed (see Table 7)

Comparative studies Fluconazole has also been compared withother antifungal agents (see Table 8) When compared with oralpolyenes it was at least equivalent in terms of prevention of super-ficial infection except in the study by Rozenberg et al suggestingthat amphotericin B (400 mg middot 4day) might more efficientlyreduce superficial candidal colonization88ndash98 Egger et al88 alsosuggested that fluconazole might reduce the need for curativeamphotericin B among neutropenic patients but taken the absence

of consensus about the use of amphotericin B in the case of per-sistent fever these results are of low clinical pertinence Flucona-zole has an excellent tolerance profile in that population withsimilar efficiency and fewer side effects than intravenous polyeneprophylaxis98

Optimal dose is not clearly defined in neutropenic patientsDosages ranging from 100 to 400 mgday were used with appar-ently the same efficacy Low doses of 50 mgday prevent super-ficial candidiasis but not invasive disease Oral administration wasapparently as efficient as the intravenous one although this pointhad never been extensively studied in appropriate comparativestudies especially as more recent studies allowed either route ofadministration

Recently two meta-analyses reviewed the data extracted fromall major studies on fluconazole prophylaxis in neutropenicpatients with or without BMT99100 Comparators were fungal-related deaths superficial and invasive candidal infections useof parenteral antifungal therapy and infection and colonizationwith fluconazole-resistant species In 2000 Kanda et al reviewed16 controlled studies involving 3734 patients99 Superficial infec-tions were clearly reduced by the use of fluconazole (combined OR023 95 CI 017ndash031) In trials involving neutropenic patientswithout BMT the benefit of fluconazole on invasive infectionsappeared only in studies in which the incidence of fungal infectionwas gt15 with a combined OR at 023 (95CI 015ndash036) Therewas also no difference in the incidence rate of invasive aspergillosisbetween control and study groups Colonization by C krusei wasmore frequent in fluconazole-treated patients (OR 201 95 CI13ndash312) Colonization by C glabrata was more frequent amongpatients with low-dose (50ndash200 mgday) regimen (OR 204 95CI 118ndash353) However there was also no difference between testand control groups in the incidence rate of invasive proven infec-tions with C krusei C glabrata or Aspergillus sp Fungal-relatedmortality was not reduced in fluconazole-treated patients In 2002Bow et al100 similarly reviewed 38 trials including 14 involvingfluconazole (4062 patients with malignant disease and severe neu-tropenia) Fluconazole regimen was associated with benefit onsuperficial and invasive fungal infections and also on fungal infec-tion-related mortality (weighted OR 053 95 CI 034ndash083)Overall mortality was not reduced and no excess of invasiveaspergillosis could be evidenced One negative issue wassubsequently identified in a retrospective study including 3002patients Viscoli et al found that absorbable antifungalprophyl axis in neutropenic patients was associated with anincreased rate of bacteraemia with an estimated OR of 142(95 CI 107ndash188)101

There is no clear international recommendation about the use offluconazole or other antifungal drugs in the non-BMT profoundlyneutropenic setting The IDSA 2002 guidelines for the use ofantimicrobial agents in neutropenic patients with cancer indicatethat lsquoroutine use of fluconazole or itraconazole for all cases ofneutropenia is not recommended However in certain circum-stances in which the frequency of systemic infection due to Calbicans is high and the frequency of systemic infection due toother Candida species and Aspergillus species is low some physi-cians may elect to administer antifungal prophylaxis (D-II)102 InGerman guidelines fluconazole prophylaxis (400 mgday) amongpatients undergoing conventional chemotherapy is a grade C-Irecommendation (poor evidence)103 French guidelines on thecare of invasive candidiasis in adults were recently updatedThe use of fluconazole prophylaxis (400 mgday) is a high

Review

392

Table

7

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

pla

ceb

oo

rn

otr

eatm

ent

inn

eutr

op

enic

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

n

atth

eE

OT

Dea

th

Lav

erd

iere

etal

81

R

DB

PC

M

C

FL

C4

00

mg

day

po

ver

sus

pla

ceb

o

wit

hin

72

h

po

st-i

nit

iati

on

of

chem

oth

erap

y

un

til

PM

N

gt5

00

mm

3

13

5(6

0B

MT

)

13

1(5

8B

MT

)

ND

ND

3

17

Plt0001

31

75

ND

Ro

tste

inet

al

84

R

DB

F

LC

40

0m

gd

ayw

ith

in7

2h

14

1(6

2B

MT

)N

D7

3

015ndash023

ND

PC

M

Cp

ov

ersu

sp

lace

bo

po

st-i

nit

iati

on

of

chem

oth

erap

yu

nti

l

PM

Ngt

50

0m

m3

13

3(5

8B

MT

)18

(P=002)

16

(P=00001)

039ndash030

fungalindex

colonization

(Plt00001)

Ker

net

al

86

R

DB

SC

FL

C4

00

mg

day

po

ver

sus

no

trea

tmen

t

36

32

ND

ND

6

6

ND

no

dif

fere

nce

Sch

affn

eret

al

87

R

DB

PC

S

C

FL

C4

00

mg

day

po

iv

ver

sus

pla

ceb

o

adm

issi

on

un

til

sust

ain

edP

MN

gt5

00

mm

3

75

76

ND

1

12

(P

=0

01

8)

8

C0

F8

9

C5

F4

8

36

(Plt00001)

6

7

Yam

acet

al

85

R

NB

SC

FL

C4

00

mg

day

po

ver

sus

no

D0

chem

oth

erap

y

un

til

PM

N

41

29

ND

ND

9

31

(Plt005)

ND

ND

trea

tmen

tgt

2middot

10

3m

m3

Ch

and

rase

kar

83

R

DB

PC

S

C

FL

C4

00

mg

day

po

ver

sus

pla

ceb

o

D0

chem

oth

erap

yo

r

con

dit

ion

ing

or

reg

imen

un

til

D+

7af

ter

PM

Ngt

10

3m

l

23

(11

BM

T)

24

(11

BM

T)

ND

34

79

(P=

00

00

2)

10

C

0

F

10

5

C5

F0

ND

17

13

Win

sto

n8

2R

D

B

PC

M

C

FL

Cp

o4

00

mg

day

po

iv

ver

sus

pla

ceb

o

D0

chem

oth

erap

y

un

til

PM

Ngt

10

3m

l

12

4

13

2

9

21

(P=

00

2)

6

15

(Plt

00

1)

4

C1

F3

8

C4

5

F

35

29

68

(P=

00

01

)

21

18

R

rand

om

ized

D

B

do

uble

bli

nd

N

B

no

tb

lin

d

PC

p

lace

bo

con

troll

ed

SC

si

ng

lece

ntr

eM

C

mult

icen

tre

FL

C

flu

conaz

ole

p

o

ora

liv

in

trav

eno

us

EO

T

end

of

trea

tmen

tN

D

no

td

on

eC

Candida

sp

F

fila

men

tou

sfu

ng

iP

MN

p

oly

mo

rph

on

ucl

ear

cell

sB

MT

b

on

em

arro

wtr

ansp

lan

tati

on

D

d

ay

Val

ues

giv

enin

bo

ldfa

cear

est

atis

tica

lly

sign

ific

ant

Review

393

Table

8

Co

mp

arat

ive

stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

oth

eran

tifu

ng

als

inn

eutr

op

enic

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

nat

the

EO

TD

eath

Morg

enst

ern

etal

89

R

SB

MC

FL

C1

00

mg

day

po

ver

sus

itra

con

azo

le

25

mg

kg

twic

e

ad

ayp

o

beg

inn

ing

con

dit

ion

ing

reg

imen

un

til

PM

N

gt1

03m

m3gt

1w

eek

22

7

(12

0B

MT

)

21

8

(11

0B

MT

)

ND

5

2

3

C1

F2

1

C1

ND

4

1

Eg

ger

etal

88

R

NB

SC

FL

C4

00

mg

day

ivp

ov

ersu

sn

yst

atin

24middot

10

6U

middot3d

ayp

o

fro

mh

osp

ital

izat

ion

in

iso

lati

on

un

itu

nti

l

end

of

neu

tro

pen

ia

43

(14

BM

T)

46

(19

BM

T)

2

4

0

0

2

4

ND

ND

Bo

dey

etal

98

R

NB

SC

FL

C4

00

mg

day

po

ver

sus

AM

B

05

mg

kgmiddot3

wee

kiv

fro

mD

0ch

emo

ther

apy

un

til

PM

Ngt

10

3m

m3

41

36

4

8

0

0

4

8

18

15

15

9

Ell

iset

al

90

R

DB

SC

FL

Cp

o2

00

mg

day

ver

sus

clo

trim

azo

le

(10

mg

qid

)+

my

cost

atin

50

00

00

IUq

id

adm

issi

on

un

til

PM

Ngt

10

3m

m3

42

(10

BM

T)

48

(13

BM

T)

95

35

(Plt

00

1)

2

13

5

21

ND

19

35

(Plt004)

Men

ich

etti

R

NB

F

LC

15

0m

gd

ayp

oD

-3to

D-1

bef

ore

42

03

5

2

15

N

D1

0

etal

93

MC

ver

sus

AM

B5

00

mg

middot4d

ayp

o

chem

oth

erap

yu

nti

l

PM

Ngt

10

3m

m3

40

05

3

2

1

0

Nin

aneet

al

92

R

NB

MC

chil

dre

n

FL

Cp

o3

mg

kg

day

ver

sus

ny

stat

inp

o

50

00

0U

kg

qid

or

AM

B

25

mg

kg

qid

po

48

hw

ith

inin

itia

tio

n

of

chem

oth

erap

y

un

til

PM

Ngt

10

3m

m3

24

5

25

7

2

8

(P=0002)

1

6

(P=0004)

1

C0

5

F0

5

2

C2

no

dif

fere

nce

inre

du

ctio

n

and

con

tro

lo

f

colo

niz

atio

n

ND

Ak

iyam

a

etal

94

R

NB

SC

FL

C2

00

mg

day

po

ver

sus

AM

B8

00

mg

middot3d

ayp

o

D0

chem

oth

erap

y

un

til

PM

Ngt

50

0m

m3

71

59

ND

ND

1

3

2

9

ND

Ph

ilp

ott

-Ho

war

d

etal

91

R

NB

MC

FL

C5

0m

gd

ayp

ov

ersu

s

AM

B2

gd

ayp

oo

r

ny

stat

in4middot

10

6U

day

bef

ore

chem

oth

erap

y

un

til

PM

Ngt

10

3m

m3

or

4w

eek

s

26

9

26

7

4

12

(P=0001)

2

9

(Plt0001)

2

C1

F1

4

C3

5

F

05

sim

ilar

ND

Meu

nie

ret

al

95

R

NB

SC

FL

Cp

o2

00

mg

day

ver

sus

AM

Bp

o4

30

mg

day

D-2

neu

tro

pen

ia

un

til

PM

Ngt

10

3m

m3

30

(9B

MT

)

29

(9B

MT

)

7

13

0

3

14

C

7

F

7

17

C

10

F7

ND

17

21

Roze

nber

g-A

rska

etal

96

R

NB

SC

FL

C5

0m

gd

ayp

ov

ersu

s

AM

B4

00

mgmiddot4

day

po

D0

neu

tro

pen

ia

un

til

PM

Ngt

50

0m

m3

25

25

ND

0 4

4

C0

F4

4

C4

F0

52

16

ND

Bra

mm

eret

al

97

C

NB

F

LC

50

mg

day

NR

12

62

7

MC

po

ver

sus

ora

l

po

lyen

es

12

24

5

(su

spec

ted

fun

gal

infe

ctio

ns)

ND

ND

ND

ND

Rr

and

om

ized

DB

do

uble

bli

nd

NB

no

tbli

nd

SB

sin

gle

bli

nd

SC

sin

gle

cen

tre

MC

mult

icen

tre

FL

Cf

luco

naz

ole

po

ora

liv

in

trav

eno

us

EO

Te

nd

oftr

eatm

ent

ND

no

tdo

ne

CC

andida

sp

Ff

ilam

ento

us

fun

gi

PM

N

po

lym

orp

ho

nu

clea

rce

lls

BM

T

bo

ne

mar

row

tran

spla

nta

tio

n

D

day

q

id

fou

rti

mes

ad

ay

Val

ues

giv

enin

bo

ldfa

cear

est

atis

tica

lly

sign

ific

ant

Review

394

grade recommendation (A-I) among allogeneic bone marrowrecipients but not in the setting of autologous BMT or acuteleukaemia (httpwwwsrlforgDataDocumentsHTMLO2_refenticls_OA-recommendations20040513asp date last accessed26 December 2005) Thus in the light of the previously describedmeta-analysis fluconazole might be appropriate in neutropenicpatients with a high risk of fungal infection ie those with longduration of neutropenia prolonged corticosteroid therapy butprobably other drugs will be better choices

Fluconazole as prophylaxis for systemic

candidiasis in ICU adults

The extent of the problem There is an increasing incidence of bothbacterial and fungal sepsis occurring in ICU patients A USstudy found that the absolute number of deaths due to invasivemycoses rose from 1557 in 1980 to 6534 in 1997104 Althoughmuch of this increase was associated with fungal infections relatedto HIV there were also marked increases in deaths due to can-didiasis aspergillosis and other mycoses in the non-HIV popula-tion A UK study looking at the outcome of candidaemia infectionsreported 187 episodes of candidaemia per 100 000 finished con-sultant episodes Of them 454 occurred in an ICU setting andC albicans was isolated in 65 of cases105 A Swiss study foundthat two-thirds of episodes of candidaemia occurred in ICU or onsurgical wards with invasive candidiasis occurring 5ndash10 timesmore frequently in an ICU setting than on other wards106

Strikingly in spite of all therapeutic innovations in the field ofantifungal therapy the crude and attributable mortality of nosoco-mial fungaemias have not decreased over the past 15 years(38)107

How are patients at risk of invasive candidiasis identified Thediagnosis of invasive candidiasis may be difficult due to the highfrequency of colonization especially in patients who are on broadspectrum antibiotics A prospective study of non-neutropenicpatients in whom Candida species were isolated found that diges-tive and respiratory samples and the isolation of non-albicansspecies were risk factors for invasive candidiasis108 Additionallythe most significant risk factors for invasive candidaemia identifiedin a surgical ICU in those who had undergone surgery were priorsurgery acute renal failure receipt of total parenteral nutrition andthe presence of a central venous catheter109 This study also foundthat administration of an antifungal agent was associated withdecreased risk for invasive candidal infection For critically illsurgical patients Pittet et al110 proposed a Candida colonizationindex based on the ratio between the number of colonized sites andthe number of sites tested Although its use in hospital practice iscomplex expensive and time-consuming this index was highlypredictive of invasive candidiasis indeed a threshold of 05 ormore correctly identified the infected patients an average of 6days before the documented candidiasis An alternative approachhas been considered using both anti-Candida antibody and antigentitres111 A high concordance between the two has been observedfor patients with invasive candidal disease compared with patientswho were only colonized with Candida Sensitivity and specificityreached 100 and 833 respectively when the two tests werecombined112

Studies that have been done A recent paper has highlighted theimportance of appropriate trial design of antifungal prophylaxisand the need for appropriate assessment of risk factors to identify

those patients who are at higher risk113 Fluconazole has previouslybeen assessed as a prophylactic agent in ITU settings with contra-dictory results

Concerns over a shift inCandida isolates that are less susceptibleor resistant to fluconazole may be balanced against the justificationof using it in appropriately identified high-risk patients114

For Three prospective randomized placebo-controlled trials haveemphasized the efficacy of fluconazole in that setting (see Table 9)In one study 260 critically ill surgical patients staying in ICU forgt3 days mainly pre-hepatic transplantation patients were ran-domly assigned to either placebo or 400 mg of fluconazole perday The risk of fungal infection was reduced by 55 in the flu-conazole group compared with the control group who experienced15 of invasive infections115 In a small study of 43 surgicalpatients with recurrent gastrointestinal leaks or perforations theuse of fluconazole prophylaxis resulted in decreased isolation ofCandida in surveillance cultures and in a decrease in candidalperitonitis 4 versus 35 with a decrease in global invasivecandidiasis (9 versus 35)116 A slightly different approachwas used in a study of 204 critically ill patients in surgical andmedical ICU where fluconazole was used as part of a selectivedigestive decontamination regimen28 These patients appear tomore closely represent a typical group of ICU patients InvasiveCandida infections occurred less frequently in 8 of the flucona-zole group compared with 20 of the placebo group and no shifttowards non-albicans species was observed

Several reviews of historical cohorts have provided similarresults A recent retrospective review in a surgical ICU comparingthe use of fluconazole prophylaxis versus a historical cohort foundthat prophylaxis decreased the incidence of candidaemia and didnot find an increase in non-albicans species117 No reduction ofmortality with fluconazole was observed Secondary Candidainfections in high-risk patients with trauma occurred in 962(145) patients who did not receive fluconazole prophylaxiscompared with 3145 (2) of a historical cohort who did118

In another randomized prospective study of bacterial septicshock fluconazole had a measurable positive impact on survivalalthough no fungal infection was diagnosed This unclear benefi-cial effect might be related to fluconazolersquos observed ability toenhance the bactericidal activity of neutrophils or to prevent Can-dida spp infection which was not diagnosed by standard bloodcultures which are known to be relatively insensitive119120

Against One group of patients at increased risk of invasivecandidiasis includes those who have undergone recent liver trans-plantation In a previously cited prospective study of 35 post-liver-transplantation patients patients with C albicans infectionswere less likely to have received antifungal prophylaxis thanthose with non-albicans Candida infections (136 versus 50P = 004) Non-albicans Candida infections and prior antifungalprophylaxis correlated with poorer outcome49 A further studylooked at 125 critically ill patients who received either fluconazoleprophylaxis or placebo during their entire stay in ICU121 Therewere no significant differences in the incidence of candidal infec-tions nor any difference in the mortality or length of stay on ICU Inthe study performed by Pelz et al115 among pre-liver-transplanta-tion patients no benefit of fluconazole on survival could be noticedalthough a clear reduction of fungal infection was observed

There are however concerns that the use of prophylacticfluconazole in critical care patients favours the emergence of

Review

395

from 77 to 30 for fluconazole and from 67 to 25 for itracona-zole Rates of invasive candidiasis were similar to those describedin the authorrsquos former study Other studies have also looked tothe contribution of fluconazole in the prophylaxis of invasivecandidiasis in liver transplant recipients

Tortorano et al55 in 1995 observed a better prevention andclearance of C albicans colonization with fluconazole than withoral amphotericin B although clearance of Candida spp was notfound to be different because of fluconazole inefficiency on non-albicans species Finally Kung et al56 in a historical comparisonreported a higher survival rate among patients receiving flucona-zole as prophylaxis (n = 45 100 mgday) compared with untreatedpatients (n = 72) 75 versus 58 As highlighted by the recentlypublished Infectious Diseases Society of America (IDSA) guide-lines fluconazole-based prophylaxis is therefore recommendedamong high-risk liver transplant recipients (with Dagger2 previouslydefined risk factors) during the early post-operative period57

This practice has been shown to be efficient in decreasing theincidence of invasive candidiasis However a shift towards non-albicans Candida species in colonization or invasive infections hasoccurred during the past 10 years with a rise from 15 to 39 afterwidespread use of fluconazole49 This trend emphasizes that the useof fluconazole as prophylaxis should be strictly targeted to high-risk patients and not be generalized to all liver recipients

Kidney transplants Given the low incidence of severe Candida spinfections in this population and the lack of specific studies the useof fluconazole is not recommended in this setting in Europe andNorth America5859

Pancreas and pancreasndashkidney transplants Intra-abdominal andurinary tract infections are the most common sites of fungal infec-tions among pancreas and pancreasndashkidney transplant recipientsIn a retrospective survey of 445 consecutive pancreatic andpancreasndashkidney transplantations fungal intra-abdominal infec-tions occurred in 41445 (92) patients and were associatedwith three times higher risk of death60 87 of all invasive fungalinfections following pancreas transplantation are caused byCandida species61 Enteric drainage procedures living relativedonor as well as previous or simultaneous kidney transplantationare associated with a higher incidence of fungal infection60 Under-lying diabetes mellitus is a predisposing condition A consistentcharacteristic of pancreas-transplanted patients with candidiasis iscolonization of the urine with Candida species62 Benedetti et al60

observed that patients receiving fluconazole prophylaxis (n = 108400 mgday for 7 days) had lower rate of fungal infection than thosewho did not (n = 327) 6 versus 10 It should be noted thatrandomized comparative studies of antifungal prophylaxisin pancreas transplantation are lacking However data from theBenedetti study suggest that fluconazole might be administeredprophylactically in that setting especially in patients who experi-enced high-risk procedures or those colonized by Candida spp

Small bowel transplantation In a retrospective study of 29 patientswith small bowel transplantation Kusne et al63 reported 20 casesof invasive fungal infections 16 of them due to Candida specieswhich was involved in 9 of all positive blood cultures Althoughnever evaluated current recommendations advocate that flucona-zole might be administered in that setting57 The use of newbiological immunosuppressants such as almetuzumab whichis associated with severe T cell cytopenia and high risk of

opportunistic infections might convey higher risk of infectionand could justify the use of preventive fluconazole64

Heart lung and heartndashlung transplantation Aspergillus is themain fungal pathogen involved in that setting Taken its lack ofefficacy on moulds fluconazole as any prophylaxis targetingCandida sp is not relevant436066

Bone marrow transplantation

Invasive fungal infections are still a major cause of morbidity andmortality among recipients of bone marrow or peripheral stem celltransplantation Allogeneic BMT recipients are at special risk66 Inthe pre-engraftment phase (day 0ndashday 30) the two major identifiedrisk factors for invasive fungal infections are (i) prolonged neu-tropenia and (ii) breaks in the mucocutaneous barrier67 Themost prevalent fungal pathogens are yeasts especially Candidaspp and as neutropenia continues Aspergillus sp Post-engraft-ment from day 30 to day 100 is characterized by impaired cell-mediated immunity Susceptibility to fungal infections is thenrelated to factors suppressing the T lymphocyte immune responseexistence of graft-versus-host disease use of corticosteroids oranti-T lymphocyte antibodies and use of T-depleted graftsThis period is more likely associated with mould infections espe-cially with Aspergillus sp and also to some extent to chronicdisseminated candidiasis68 Two main randomized double-blindstudies have demonstrated the benefit of fluconazole amongBMT recipients (allogeneic + autologous) as shown in theTable 56970 At the dose of 400 mgday fluconazole was ableto significantly decrease the risk of superficial and invasive can-didal infections and the overall number of deaths related to fungaldisease Furthermore fluconazole was able to reduce the fungalcolonization at the endpoint of evaluation Slavin et al showed asignificant decrease of overall mortality at day 110 post-allogeneictransplantation after a 75 day regimen of fluconazole70 Confirma-tion and extension of this benefit was shown by Marr et al71 on thesame cohort with the survival benefit persisting after up to 8 yearsof follow-up Indeed administration of placebo was shown to be anindependent factor for poor survival

Fluconazole has also been compared with other antifungal drugsin allogeneic and autologous BMT (see Table 6) It has been shownto be as efficient as intravenous amphotericin B (02 mgkgday) forlowering Candida colonization and superficial and invasive fungalinfections in randomized non-blinded trials73 Three randomizednon-blinded studies have compared the efficacy of itraconazoleand fluconazole in bone marrow recipients with conflictingresults74ndash76 Annaloro et al74 did not observe any difference ininfection-related death invasive candidiasis or in the need forcurative doses of amphotericin B Winston et al75 observed sta-tistically more invasive fungal infections in the fluconazole groupthan in the itraconazole one (n = 138 25 versus 9) all of themrelated to non-albicans Candida species and moulds (Aspergillussp Fusarium sp and Rhizopus sp) However no difference insurvival could be detected Tolerance of itraconazole was lowerthan that of fluconazole Marr et al76 failed to show any superiorityof itraconazole in an intention-to-treat analysis whereas on-treat-ment analysis revealed a higher rate of invasive fungal infection inthe fluconazole group (mostly invasive mould infections) How-ever only one study has shown increased incidence of infectionsdue to Aspergillus species or other moulds in patients treated withfluconazole79 Therefore although with a spectrum of activity

Review

389

Table

5

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

pla

ceb

oo

rn

otr

eatm

ent

inal

log

enei

can

dau

tolo

go

us

bo

ne

mar

row

tran

spla

nt

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts(a

uto

)

Candida

sp

colo

niz

atio

nat

the

EO

T

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Dea

th

rela

ted

toIF

I

Ov

eral

l

mo

rtal

ity

Mar

ret

al

71

R

DB

PC

S

C

FL

Cp

o4

00

mg

day

firs

td

ayw

ith

PM

Nlt

50

0m

m3

15

2(1

8)

ND

ND

C3

9

C1

F8

55

ver

sus

pla

ceb

ou

nti

lD

+7

51

48

(17

)C20

(Plt0001)

14

C8

F6

(P=0001)

72

(P=

00

00

1)

Sla

vin

etal

70

R

DB

PC

S

C

FL

Cp

o4

00

mg

day

Fir

std

ayw

ith

PM

Nlt

50

0m

m3

15

2(1

8)

77

0

7

7

Clt1

F7

20

ver

sus

pla

ceb

ou

nti

lD

+7

51

48

(17

)86 (P

=0037)

7

(Plt0001)

18 (P

=0004)

13

C9

F4

35 (P

=0004)

Ala

ng

aden

etal

72

HC

FL

Cp

o1

00

or

2w

eek

sb

efo

re1

12

(28

)70

4

9

20

0m

gd

ay

ver

sus

no

trea

tmen

t

BM

Tu

nti

l

PM

Ngt

50

0m

m3

79

(40

)82

ND

10 (P

lt005)

ND

18

Go

od

man

etal

69

R

DB

PC

M

C

FL

Cp

o4

00

mg

day

ver

sus

pla

ceb

o

firs

td

ay

con

dit

ion

ing

reg

imen

17

9(8

6)

30

8

3

C2

F1

1

31

un

til

eng

raft

men

t

(PM

Ngt

10

3m

m3)

17

7(1

00

)67 (P

lt0001)

33 (P

lt0001)

16

C14

F2

(Plt0001)

6

26

Rr

andom

ized

Ret

rre

trosp

ecti

ve

DB

double

bli

ndP

Cp

lace

bo

contr

oll

edD

day

SC

sin

gle

centr

eM

Cm

ult

icen

tre

HC

his

tori

calc

om

par

ison

au

toa

uto

logo

us

bo

ne

mar

row

FL

Cf

luco

naz

ole

po

ora

lE

OT

en

do

ftr

eatm

ent

IFI

inv

asiv

efu

ng

alin

fect

ion

N

Dn

ot

do

ne

CCandida

sp

Ffi

lam

ento

us

fun

gi

PM

Np

oly

mo

rph

on

ucl

ear

cell

sB

MT

b

on

em

arro

wtr

ansp

lan

tati

on

V

alu

esg

iven

inb

old

face

are

stat

isti

call

ysi

gnif

ican

t

Review

390

Table

6

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

oth

eran

tifu

ng

als

inal

log

enei

can

dau

tolo

go

us

bo

ne

mar

row

tran

spla

nt

pat

ien

ts

Ref

eren

ceS

tud

yd

esig

nR

egim

enD

ura

tio

no

ftr

eatm

ent

Nu

mb

ero

f

pat

ien

ts

(au

to)

Su

per

fici

al

Candida

sp

infe

ctio

ns

Inv

asiv

e

fun

gal

infe

ctio

ns

Candida

sp

colo

niz

atio

n

atth

eE

OT

Dea

th

rela

ted

toIF

I

Ov

eral

l

dea

th

van

Bu

riket

al

79

R

DB

M

CF

LC

po

40

0m

gd

ay

ver

sus

mic

afu

ng

in

(50

mg

day

)

48

hb

efo

reco

nd

itio

nin

g

reg

imen

un

til

eng

raft

men

t

45

7(2

01

)

42

5(2

03

)

ND

24

C

04

F2

16

C

09

F1

7

34

52

lt1

lt1

6

4

Mar

ret

al

76

R

NB

S

CF

LC

po

or

iv

40

0m

gd

ayv

ersu

s

itra

con

azo

le

75

mg

kg

po

20

0m

gd

ay

con

dit

ion

ing

reg

imen

toD

-12

0(n

=1

87

)

D-0

toD

-12

0(n

=1

02

)

14

8

15

1

ND

19

C

3

F1

6

18

C

3

F

15

ND

7

8

31

39

Win

sto

net

al

75

R

NB

M

CF

LC

po

or

iv4

00

mg

day

ver

sus

itra

con

azo

le

iv2

00

mg

day

or

po

25

mg

kg

day

middot3d

ay

D-1

toD

-10

0

afte

rB

MT

68

72

3

4

25

9

(P=001)

ND

ND

42

45

Ko

het

al

22

7R

N

B

SC

FL

Cp

o2

00

mg

day

ver

sus

amp

ho

teri

cin

B

iv0

2m

gk

gd

ay

24

hb

efo

reco

nd

itio

nin

g

reg

imen

un

til

eng

raft

men

t

(PM

Ngt

50

0m

m3gt

3d

ays)

10

0(2

6)

86

(20

)

1

5

12

13

ND

6

7

22

30

Wo

lffet

al

73

R

NB

M

CF

LC

po

40

0m

gd

ay

ver

sus

amp

ho

teri

cin

B

iv0

2m

gk

gd

ay

D-1

pre

con

dit

ion

ing

reg

imen

un

til

eng

raft

men

t

(PM

Ngt

50

0m

m3)

19

6(1

42

)

15

9(1

10

)

ND

26

2

27

43

3

1

12

12

An

nal

oro

etal

74

R

NB

S

CF

LC

po

30

0m

gd

ay

ver

sus

FL

Cp

o

50

mg

day

ver

sus

itra

con

azo

le4

00

mg

day

D-1

pre

con

dit

ion

ing

reg

imen

un

til

eng

raft

men

t

(PM

Ngt

50

0m

m3)

28

30

31

ND

4

3

13

ND

no

dif

fere

nce

ND

Glu

ckm

anet

al

22

8R

N

B

SC

FL

Cp

oi

v

10

0m

gd

ay

ver

sus

ket

oco

naz

ole

40

0m

gd

ay

Dndash

8to

D+

90

afte

rB

MT

30

29

3

11

10

7

47

41

ND

ND

Rra

ndom

ized

D

Bdouble

bli

nd

NB

not

bli

nd

PC

pla

cebo

contr

oll

ed

SC

si

ngle

centr

eM

Cm

ult

icen

tre

FL

Cfl

uco

naz

ole

poora

liv

in

trav

eno

us

EO

Ten

do

ftr

eatm

ent

ND

n

ot

do

ne

CCandida

sp

F

fila

men

tous

fungi

PM

N

poly

morp

honucl

ear

cell

sB

MT

bone

mar

row

tran

spla

nta

tion

D

day

V

alues

giv

enin

bold

face

are

stat

isti

call

ysi

gnif

ican

t

Review

391

limited to yeasts fluconazole has been widely adopted as an effec-tive and safe therapy Its use is now recommended from the day ofhaematopoietic stem cell transplantation until engraftment inguidelines for prevention of opportunistic infections among allo-geneic bone marrow recipients67 The optimal dose of fluconazolein that setting is not clearly determined The posology of 400 mgday is recommended by the IDSA However lower doses have beenshown to be similarly effective in reducing the risk of invasiveinfections and candidal colonization7176 MacMillan et al77 in alarge cohort of 253 patients demonstrated similar efficiency of highand low dosages of fluconazole (200 and 400 mgday) on the rate offungal colonization and infection No increase of reduced suscep-tibility in isolates of Candida was seen at the low doses Theadoption of fluconazole as prophylactic regimen in BMT has raisedconcern about a shift of colonization towards azole-resistant strainsof Candida sp Indeed Marr et al78 observed that out of 585patients undergoing BMT with prophylactic fluconazole 44were colonized with Candida sp during the procedure half ofthem with a species other than C albicans However no increasein invasive candidiasis or in deaths related to non-albicans Candidainfections could be observed Very recently van Burik et al79 in alarge randomized double-blind multicentre study on 882 patientsobserved superior efficacy of the echinocandin micafungin (50 mgday) over fluconazole (400 mgday) on the prevention of invasivefungal infection among bone marrow recipients 80 of successversus 73 Further costndashbenefit studies are required to determinewhether micafungin could be an alternative to fluconazole in thatsetting particularly as fluconazole is now generic

Fluconazole for prophylaxis of Candida infections in

neutropenic patients

Neutropenic patients with haematological malignancies are at highrisk for developing invasive and superficial mycoses However allof them do not share the same risk of fungal infection

Prolonged deep neutropenia as observed in intensiveinduction or salvage regimens for acute leukaemia use of corti-costeroids and exposure to high-dose cytosine arabinoside or tomonoclonal antibodies (anti-CD52) are deeply immunosuppress-ing conditions facilitating the emergence of invasive fungalinfections80

Studies versus placebo Seven studies have shown the efficacy offluconazole in the setting of fungal prophylaxis among neutropenicpatients (excluding BMT) including five randomized double-blind placebo-controlled trials81ndash87 Indeed fluconazole hasbeen shown to significantly reduce Candida species colonizationsuperficial infections invasive proven candidal infections as wellas fungal-related mortality A broad range of doses were used inthese studies ranging from 50 to 400 mgday However no benefiton overall mortality has been observed (see Table 7)

Comparative studies Fluconazole has also been compared withother antifungal agents (see Table 8) When compared with oralpolyenes it was at least equivalent in terms of prevention of super-ficial infection except in the study by Rozenberg et al suggestingthat amphotericin B (400 mg middot 4day) might more efficientlyreduce superficial candidal colonization88ndash98 Egger et al88 alsosuggested that fluconazole might reduce the need for curativeamphotericin B among neutropenic patients but taken the absence

of consensus about the use of amphotericin B in the case of per-sistent fever these results are of low clinical pertinence Flucona-zole has an excellent tolerance profile in that population withsimilar efficiency and fewer side effects than intravenous polyeneprophylaxis98

Optimal dose is not clearly defined in neutropenic patientsDosages ranging from 100 to 400 mgday were used with appar-ently the same efficacy Low doses of 50 mgday prevent super-ficial candidiasis but not invasive disease Oral administration wasapparently as efficient as the intravenous one although this pointhad never been extensively studied in appropriate comparativestudies especially as more recent studies allowed either route ofadministration

Recently two meta-analyses reviewed the data extracted fromall major studies on fluconazole prophylaxis in neutropenicpatients with or without BMT99100 Comparators were fungal-related deaths superficial and invasive candidal infections useof parenteral antifungal therapy and infection and colonizationwith fluconazole-resistant species In 2000 Kanda et al reviewed16 controlled studies involving 3734 patients99 Superficial infec-tions were clearly reduced by the use of fluconazole (combined OR023 95 CI 017ndash031) In trials involving neutropenic patientswithout BMT the benefit of fluconazole on invasive infectionsappeared only in studies in which the incidence of fungal infectionwas gt15 with a combined OR at 023 (95CI 015ndash036) Therewas also no difference in the incidence rate of invasive aspergillosisbetween control and study groups Colonization by C krusei wasmore frequent in fluconazole-treated patients (OR 201 95 CI13ndash312) Colonization by C glabrata was more frequent amongpatients with low-dose (50ndash200 mgday) regimen (OR 204 95CI 118ndash353) However there was also no difference between testand control groups in the incidence rate of invasive proven infec-tions with C krusei C glabrata or Aspergillus sp Fungal-relatedmortality was not reduced in fluconazole-treated patients In 2002Bow et al100 similarly reviewed 38 trials including 14 involvingfluconazole (4062 patients with malignant disease and severe neu-tropenia) Fluconazole regimen was associated with benefit onsuperficial and invasive fungal infections and also on fungal infec-tion-related mortality (weighted OR 053 95 CI 034ndash083)Overall mortality was not reduced and no excess of invasiveaspergillosis could be evidenced One negative issue wassubsequently identified in a retrospective study including 3002patients Viscoli et al found that absorbable antifungalprophyl axis in neutropenic patients was associated with anincreased rate of bacteraemia with an estimated OR of 142(95 CI 107ndash188)101

There is no clear international recommendation about the use offluconazole or other antifungal drugs in the non-BMT profoundlyneutropenic setting The IDSA 2002 guidelines for the use ofantimicrobial agents in neutropenic patients with cancer indicatethat lsquoroutine use of fluconazole or itraconazole for all cases ofneutropenia is not recommended However in certain circum-stances in which the frequency of systemic infection due to Calbicans is high and the frequency of systemic infection due toother Candida species and Aspergillus species is low some physi-cians may elect to administer antifungal prophylaxis (D-II)102 InGerman guidelines fluconazole prophylaxis (400 mgday) amongpatients undergoing conventional chemotherapy is a grade C-Irecommendation (poor evidence)103 French guidelines on thecare of invasive candidiasis in adults were recently updatedThe use of fluconazole prophylaxis (400 mgday) is a high

Review

392

Table

7

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

pla

ceb

oo

rn

otr

eatm

ent

inn

eutr

op

enic

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

n

atth

eE

OT

Dea

th

Lav

erd

iere

etal

81

R

DB

PC

M

C

FL

C4

00

mg

day

po

ver

sus

pla

ceb

o

wit

hin

72

h

po

st-i

nit

iati

on

of

chem

oth

erap

y

un

til

PM

N

gt5

00

mm

3

13

5(6

0B

MT

)

13

1(5

8B

MT

)

ND

ND

3

17

Plt0001

31

75

ND

Ro

tste

inet

al

84

R

DB

F

LC

40

0m

gd

ayw

ith

in7

2h

14

1(6

2B

MT

)N

D7

3

015ndash023

ND

PC

M

Cp

ov

ersu

sp

lace

bo

po

st-i

nit

iati

on

of

chem

oth

erap

yu

nti

l

PM

Ngt

50

0m

m3

13

3(5

8B

MT

)18

(P=002)

16

(P=00001)

039ndash030

fungalindex

colonization

(Plt00001)

Ker

net

al

86

R

DB

SC

FL

C4

00

mg

day

po

ver

sus

no

trea

tmen

t

36

32

ND

ND

6

6

ND

no

dif

fere

nce

Sch

affn

eret

al

87

R

DB

PC

S

C

FL

C4

00

mg

day

po

iv

ver

sus

pla

ceb

o

adm

issi

on

un

til

sust

ain

edP

MN

gt5

00

mm

3

75

76

ND

1

12

(P

=0

01

8)

8

C0

F8

9

C5

F4

8

36

(Plt00001)

6

7

Yam

acet

al

85

R

NB

SC

FL

C4

00

mg

day

po

ver

sus

no

D0

chem

oth

erap

y

un

til

PM

N

41

29

ND

ND

9

31

(Plt005)

ND

ND

trea

tmen

tgt

2middot

10

3m

m3

Ch

and

rase

kar

83

R

DB

PC

S

C

FL

C4

00

mg

day

po

ver

sus

pla

ceb

o

D0

chem

oth

erap

yo

r

con

dit

ion

ing

or

reg

imen

un

til

D+

7af

ter

PM

Ngt

10

3m

l

23

(11

BM

T)

24

(11

BM

T)

ND

34

79

(P=

00

00

2)

10

C

0

F

10

5

C5

F0

ND

17

13

Win

sto

n8

2R

D

B

PC

M

C

FL

Cp

o4

00

mg

day

po

iv

ver

sus

pla

ceb

o

D0

chem

oth

erap

y

un

til

PM

Ngt

10

3m

l

12

4

13

2

9

21

(P=

00

2)

6

15

(Plt

00

1)

4

C1

F3

8

C4

5

F

35

29

68

(P=

00

01

)

21

18

R

rand

om

ized

D

B

do

uble

bli

nd

N

B

no

tb

lin

d

PC

p

lace

bo

con

troll

ed

SC

si

ng

lece

ntr

eM

C

mult

icen

tre

FL

C

flu

conaz

ole

p

o

ora

liv

in

trav

eno

us

EO

T

end

of

trea

tmen

tN

D

no

td

on

eC

Candida

sp

F

fila

men

tou

sfu

ng

iP

MN

p

oly

mo

rph

on

ucl

ear

cell

sB

MT

b

on

em

arro

wtr

ansp

lan

tati

on

D

d

ay

Val

ues

giv

enin

bo

ldfa

cear

est

atis

tica

lly

sign

ific

ant

Review

393

Table

8

Co

mp

arat

ive

stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

oth

eran

tifu

ng

als

inn

eutr

op

enic

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

nat

the

EO

TD

eath

Morg

enst

ern

etal

89

R

SB

MC

FL

C1

00

mg

day

po

ver

sus

itra

con

azo

le

25

mg

kg

twic

e

ad

ayp

o

beg

inn

ing

con

dit

ion

ing

reg

imen

un

til

PM

N

gt1

03m

m3gt

1w

eek

22

7

(12

0B

MT

)

21

8

(11

0B

MT

)

ND

5

2

3

C1

F2

1

C1

ND

4

1

Eg

ger

etal

88

R

NB

SC

FL

C4

00

mg

day

ivp

ov

ersu

sn

yst

atin

24middot

10

6U

middot3d

ayp

o

fro

mh

osp

ital

izat

ion

in

iso

lati

on

un

itu

nti

l

end

of

neu

tro

pen

ia

43

(14

BM

T)

46

(19

BM

T)

2

4

0

0

2

4

ND

ND

Bo

dey

etal

98

R

NB

SC

FL

C4

00

mg

day

po

ver

sus

AM

B

05

mg

kgmiddot3

wee

kiv

fro

mD

0ch

emo

ther

apy

un

til

PM

Ngt

10

3m

m3

41

36

4

8

0

0

4

8

18

15

15

9

Ell

iset

al

90

R

DB

SC

FL

Cp

o2

00

mg

day

ver

sus

clo

trim

azo

le

(10

mg

qid

)+

my

cost

atin

50

00

00

IUq

id

adm

issi

on

un

til

PM

Ngt

10

3m

m3

42

(10

BM

T)

48

(13

BM

T)

95

35

(Plt

00

1)

2

13

5

21

ND

19

35

(Plt004)

Men

ich

etti

R

NB

F

LC

15

0m

gd

ayp

oD

-3to

D-1

bef

ore

42

03

5

2

15

N

D1

0

etal

93

MC

ver

sus

AM

B5

00

mg

middot4d

ayp

o

chem

oth

erap

yu

nti

l

PM

Ngt

10

3m

m3

40

05

3

2

1

0

Nin

aneet

al

92

R

NB

MC

chil

dre

n

FL

Cp

o3

mg

kg

day

ver

sus

ny

stat

inp

o

50

00

0U

kg

qid

or

AM

B

25

mg

kg

qid

po

48

hw

ith

inin

itia

tio

n

of

chem

oth

erap

y

un

til

PM

Ngt

10

3m

m3

24

5

25

7

2

8

(P=0002)

1

6

(P=0004)

1

C0

5

F0

5

2

C2

no

dif

fere

nce

inre

du

ctio

n

and

con

tro

lo

f

colo

niz

atio

n

ND

Ak

iyam

a

etal

94

R

NB

SC

FL

C2

00

mg

day

po

ver

sus

AM

B8

00

mg

middot3d

ayp

o

D0

chem

oth

erap

y

un

til

PM

Ngt

50

0m

m3

71

59

ND

ND

1

3

2

9

ND

Ph

ilp

ott

-Ho

war

d

etal

91

R

NB

MC

FL

C5

0m

gd

ayp

ov

ersu

s

AM

B2

gd

ayp

oo

r

ny

stat

in4middot

10

6U

day

bef

ore

chem

oth

erap

y

un

til

PM

Ngt

10

3m

m3

or

4w

eek

s

26

9

26

7

4

12

(P=0001)

2

9

(Plt0001)

2

C1

F1

4

C3

5

F

05

sim

ilar

ND

Meu

nie

ret

al

95

R

NB

SC

FL

Cp

o2

00

mg

day

ver

sus

AM

Bp

o4

30

mg

day

D-2

neu

tro

pen

ia

un

til

PM

Ngt

10

3m

m3

30

(9B

MT

)

29

(9B

MT

)

7

13

0

3

14

C

7

F

7

17

C

10

F7

ND

17

21

Roze

nber

g-A

rska

etal

96

R

NB

SC

FL

C5

0m

gd

ayp

ov

ersu

s

AM

B4

00

mgmiddot4

day

po

D0

neu

tro

pen

ia

un

til

PM

Ngt

50

0m

m3

25

25

ND

0 4

4

C0

F4

4

C4

F0

52

16

ND

Bra

mm

eret

al

97

C

NB

F

LC

50

mg

day

NR

12

62

7

MC

po

ver

sus

ora

l

po

lyen

es

12

24

5

(su

spec

ted

fun

gal

infe

ctio

ns)

ND

ND

ND

ND

Rr

and

om

ized

DB

do

uble

bli

nd

NB

no

tbli

nd

SB

sin

gle

bli

nd

SC

sin

gle

cen

tre

MC

mult

icen

tre

FL

Cf

luco

naz

ole

po

ora

liv

in

trav

eno

us

EO

Te

nd

oftr

eatm

ent

ND

no

tdo

ne

CC

andida

sp

Ff

ilam

ento

us

fun

gi

PM

N

po

lym

orp

ho

nu

clea

rce

lls

BM

T

bo

ne

mar

row

tran

spla

nta

tio

n

D

day

q

id

fou

rti

mes

ad

ay

Val

ues

giv

enin

bo

ldfa

cear

est

atis

tica

lly

sign

ific

ant

Review

394

grade recommendation (A-I) among allogeneic bone marrowrecipients but not in the setting of autologous BMT or acuteleukaemia (httpwwwsrlforgDataDocumentsHTMLO2_refenticls_OA-recommendations20040513asp date last accessed26 December 2005) Thus in the light of the previously describedmeta-analysis fluconazole might be appropriate in neutropenicpatients with a high risk of fungal infection ie those with longduration of neutropenia prolonged corticosteroid therapy butprobably other drugs will be better choices

Fluconazole as prophylaxis for systemic

candidiasis in ICU adults

The extent of the problem There is an increasing incidence of bothbacterial and fungal sepsis occurring in ICU patients A USstudy found that the absolute number of deaths due to invasivemycoses rose from 1557 in 1980 to 6534 in 1997104 Althoughmuch of this increase was associated with fungal infections relatedto HIV there were also marked increases in deaths due to can-didiasis aspergillosis and other mycoses in the non-HIV popula-tion A UK study looking at the outcome of candidaemia infectionsreported 187 episodes of candidaemia per 100 000 finished con-sultant episodes Of them 454 occurred in an ICU setting andC albicans was isolated in 65 of cases105 A Swiss study foundthat two-thirds of episodes of candidaemia occurred in ICU or onsurgical wards with invasive candidiasis occurring 5ndash10 timesmore frequently in an ICU setting than on other wards106

Strikingly in spite of all therapeutic innovations in the field ofantifungal therapy the crude and attributable mortality of nosoco-mial fungaemias have not decreased over the past 15 years(38)107

How are patients at risk of invasive candidiasis identified Thediagnosis of invasive candidiasis may be difficult due to the highfrequency of colonization especially in patients who are on broadspectrum antibiotics A prospective study of non-neutropenicpatients in whom Candida species were isolated found that diges-tive and respiratory samples and the isolation of non-albicansspecies were risk factors for invasive candidiasis108 Additionallythe most significant risk factors for invasive candidaemia identifiedin a surgical ICU in those who had undergone surgery were priorsurgery acute renal failure receipt of total parenteral nutrition andthe presence of a central venous catheter109 This study also foundthat administration of an antifungal agent was associated withdecreased risk for invasive candidal infection For critically illsurgical patients Pittet et al110 proposed a Candida colonizationindex based on the ratio between the number of colonized sites andthe number of sites tested Although its use in hospital practice iscomplex expensive and time-consuming this index was highlypredictive of invasive candidiasis indeed a threshold of 05 ormore correctly identified the infected patients an average of 6days before the documented candidiasis An alternative approachhas been considered using both anti-Candida antibody and antigentitres111 A high concordance between the two has been observedfor patients with invasive candidal disease compared with patientswho were only colonized with Candida Sensitivity and specificityreached 100 and 833 respectively when the two tests werecombined112

Studies that have been done A recent paper has highlighted theimportance of appropriate trial design of antifungal prophylaxisand the need for appropriate assessment of risk factors to identify

those patients who are at higher risk113 Fluconazole has previouslybeen assessed as a prophylactic agent in ITU settings with contra-dictory results

Concerns over a shift inCandida isolates that are less susceptibleor resistant to fluconazole may be balanced against the justificationof using it in appropriately identified high-risk patients114

For Three prospective randomized placebo-controlled trials haveemphasized the efficacy of fluconazole in that setting (see Table 9)In one study 260 critically ill surgical patients staying in ICU forgt3 days mainly pre-hepatic transplantation patients were ran-domly assigned to either placebo or 400 mg of fluconazole perday The risk of fungal infection was reduced by 55 in the flu-conazole group compared with the control group who experienced15 of invasive infections115 In a small study of 43 surgicalpatients with recurrent gastrointestinal leaks or perforations theuse of fluconazole prophylaxis resulted in decreased isolation ofCandida in surveillance cultures and in a decrease in candidalperitonitis 4 versus 35 with a decrease in global invasivecandidiasis (9 versus 35)116 A slightly different approachwas used in a study of 204 critically ill patients in surgical andmedical ICU where fluconazole was used as part of a selectivedigestive decontamination regimen28 These patients appear tomore closely represent a typical group of ICU patients InvasiveCandida infections occurred less frequently in 8 of the flucona-zole group compared with 20 of the placebo group and no shifttowards non-albicans species was observed

Several reviews of historical cohorts have provided similarresults A recent retrospective review in a surgical ICU comparingthe use of fluconazole prophylaxis versus a historical cohort foundthat prophylaxis decreased the incidence of candidaemia and didnot find an increase in non-albicans species117 No reduction ofmortality with fluconazole was observed Secondary Candidainfections in high-risk patients with trauma occurred in 962(145) patients who did not receive fluconazole prophylaxiscompared with 3145 (2) of a historical cohort who did118

In another randomized prospective study of bacterial septicshock fluconazole had a measurable positive impact on survivalalthough no fungal infection was diagnosed This unclear benefi-cial effect might be related to fluconazolersquos observed ability toenhance the bactericidal activity of neutrophils or to prevent Can-dida spp infection which was not diagnosed by standard bloodcultures which are known to be relatively insensitive119120

Against One group of patients at increased risk of invasivecandidiasis includes those who have undergone recent liver trans-plantation In a previously cited prospective study of 35 post-liver-transplantation patients patients with C albicans infectionswere less likely to have received antifungal prophylaxis thanthose with non-albicans Candida infections (136 versus 50P = 004) Non-albicans Candida infections and prior antifungalprophylaxis correlated with poorer outcome49 A further studylooked at 125 critically ill patients who received either fluconazoleprophylaxis or placebo during their entire stay in ICU121 Therewere no significant differences in the incidence of candidal infec-tions nor any difference in the mortality or length of stay on ICU Inthe study performed by Pelz et al115 among pre-liver-transplanta-tion patients no benefit of fluconazole on survival could be noticedalthough a clear reduction of fungal infection was observed

There are however concerns that the use of prophylacticfluconazole in critical care patients favours the emergence of

Review

395

Table

5

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

pla

ceb

oo

rn

otr

eatm

ent

inal

log

enei

can

dau

tolo

go

us

bo

ne

mar

row

tran

spla

nt

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts(a

uto

)

Candida

sp

colo

niz

atio

nat

the

EO

T

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Dea

th

rela

ted

toIF

I

Ov

eral

l

mo

rtal

ity

Mar

ret

al

71

R

DB

PC

S

C

FL

Cp

o4

00

mg

day

firs

td

ayw

ith

PM

Nlt

50

0m

m3

15

2(1

8)

ND

ND

C3

9

C1

F8

55

ver

sus

pla

ceb

ou

nti

lD

+7

51

48

(17

)C20

(Plt0001)

14

C8

F6

(P=0001)

72

(P=

00

00

1)

Sla

vin

etal

70

R

DB

PC

S

C

FL

Cp

o4

00

mg

day

Fir

std

ayw

ith

PM

Nlt

50

0m

m3

15

2(1

8)

77

0

7

7

Clt1

F7

20

ver

sus

pla

ceb

ou

nti

lD

+7

51

48

(17

)86 (P

=0037)

7

(Plt0001)

18 (P

=0004)

13

C9

F4

35 (P

=0004)

Ala

ng

aden

etal

72

HC

FL

Cp

o1

00

or

2w

eek

sb

efo

re1

12

(28

)70

4

9

20

0m

gd

ay

ver

sus

no

trea

tmen

t

BM

Tu

nti

l

PM

Ngt

50

0m

m3

79

(40

)82

ND

10 (P

lt005)

ND

18

Go

od

man

etal

69

R

DB

PC

M

C

FL

Cp

o4

00

mg

day

ver

sus

pla

ceb

o

firs

td

ay

con

dit

ion

ing

reg

imen

17

9(8

6)

30

8

3

C2

F1

1

31

un

til

eng

raft

men

t

(PM

Ngt

10

3m

m3)

17

7(1

00

)67 (P

lt0001)

33 (P

lt0001)

16

C14

F2

(Plt0001)

6

26

Rr

andom

ized

Ret

rre

trosp

ecti

ve

DB

double

bli

ndP

Cp

lace

bo

contr

oll

edD

day

SC

sin

gle

centr

eM

Cm

ult

icen

tre

HC

his

tori

calc

om

par

ison

au

toa

uto

logo

us

bo

ne

mar

row

FL

Cf

luco

naz

ole

po

ora

lE

OT

en

do

ftr

eatm

ent

IFI

inv

asiv

efu

ng

alin

fect

ion

N

Dn

ot

do

ne

CCandida

sp

Ffi

lam

ento

us

fun

gi

PM

Np

oly

mo

rph

on

ucl

ear

cell

sB

MT

b

on

em

arro

wtr

ansp

lan

tati

on

V

alu

esg

iven

inb

old

face

are

stat

isti

call

ysi

gnif

ican

t

Review

390

Table

6

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

oth

eran

tifu

ng

als

inal

log

enei

can

dau

tolo

go

us

bo

ne

mar

row

tran

spla

nt

pat

ien

ts

Ref

eren

ceS

tud

yd

esig

nR

egim

enD

ura

tio

no

ftr

eatm

ent

Nu

mb

ero

f

pat

ien

ts

(au

to)

Su

per

fici

al

Candida

sp

infe

ctio

ns

Inv

asiv

e

fun

gal

infe

ctio

ns

Candida

sp

colo

niz

atio

n

atth

eE

OT

Dea

th

rela

ted

toIF

I

Ov

eral

l

dea

th

van

Bu

riket

al

79

R

DB

M

CF

LC

po

40

0m

gd

ay

ver

sus

mic

afu

ng

in

(50

mg

day

)

48

hb

efo

reco

nd

itio

nin

g

reg

imen

un

til

eng

raft

men

t

45

7(2

01

)

42

5(2

03

)

ND

24

C

04

F2

16

C

09

F1

7

34

52

lt1

lt1

6

4

Mar

ret

al

76

R

NB

S

CF

LC

po

or

iv

40

0m

gd

ayv

ersu

s

itra

con

azo

le

75

mg

kg

po

20

0m

gd

ay

con

dit

ion

ing

reg

imen

toD

-12

0(n

=1

87

)

D-0

toD

-12

0(n

=1

02

)

14

8

15

1

ND

19

C

3

F1

6

18

C

3

F

15

ND

7

8

31

39

Win

sto

net

al

75

R

NB

M

CF

LC

po

or

iv4

00

mg

day

ver

sus

itra

con

azo

le

iv2

00

mg

day

or

po

25

mg

kg

day

middot3d

ay

D-1

toD

-10

0

afte

rB

MT

68

72

3

4

25

9

(P=001)

ND

ND

42

45

Ko

het

al

22

7R

N

B

SC

FL

Cp

o2

00

mg

day

ver

sus

amp

ho

teri

cin

B

iv0

2m

gk

gd

ay

24

hb

efo

reco

nd

itio

nin

g

reg

imen

un

til

eng

raft

men

t

(PM

Ngt

50

0m

m3gt

3d

ays)

10

0(2

6)

86

(20

)

1

5

12

13

ND

6

7

22

30

Wo

lffet

al

73

R

NB

M

CF

LC

po

40

0m

gd

ay

ver

sus

amp

ho

teri

cin

B

iv0

2m

gk

gd

ay

D-1

pre

con

dit

ion

ing

reg

imen

un

til

eng

raft

men

t

(PM

Ngt

50

0m

m3)

19

6(1

42

)

15

9(1

10

)

ND

26

2

27

43

3

1

12

12

An

nal

oro

etal

74

R

NB

S

CF

LC

po

30

0m

gd

ay

ver

sus

FL

Cp

o

50

mg

day

ver

sus

itra

con

azo

le4

00

mg

day

D-1

pre

con

dit

ion

ing

reg

imen

un

til

eng

raft

men

t

(PM

Ngt

50

0m

m3)

28

30

31

ND

4

3

13

ND

no

dif

fere

nce

ND

Glu

ckm

anet

al

22

8R

N

B

SC

FL

Cp

oi

v

10

0m

gd

ay

ver

sus

ket

oco

naz

ole

40

0m

gd

ay

Dndash

8to

D+

90

afte

rB

MT

30

29

3

11

10

7

47

41

ND

ND

Rra

ndom

ized

D

Bdouble

bli

nd

NB

not

bli

nd

PC

pla

cebo

contr

oll

ed

SC

si

ngle

centr

eM

Cm

ult

icen

tre

FL

Cfl

uco

naz

ole

poora

liv

in

trav

eno

us

EO

Ten

do

ftr

eatm

ent

ND

n

ot

do

ne

CCandida

sp

F

fila

men

tous

fungi

PM

N

poly

morp

honucl

ear

cell

sB

MT

bone

mar

row

tran

spla

nta

tion

D

day

V

alues

giv

enin

bold

face

are

stat

isti

call

ysi

gnif

ican

t

Review

391

limited to yeasts fluconazole has been widely adopted as an effec-tive and safe therapy Its use is now recommended from the day ofhaematopoietic stem cell transplantation until engraftment inguidelines for prevention of opportunistic infections among allo-geneic bone marrow recipients67 The optimal dose of fluconazolein that setting is not clearly determined The posology of 400 mgday is recommended by the IDSA However lower doses have beenshown to be similarly effective in reducing the risk of invasiveinfections and candidal colonization7176 MacMillan et al77 in alarge cohort of 253 patients demonstrated similar efficiency of highand low dosages of fluconazole (200 and 400 mgday) on the rate offungal colonization and infection No increase of reduced suscep-tibility in isolates of Candida was seen at the low doses Theadoption of fluconazole as prophylactic regimen in BMT has raisedconcern about a shift of colonization towards azole-resistant strainsof Candida sp Indeed Marr et al78 observed that out of 585patients undergoing BMT with prophylactic fluconazole 44were colonized with Candida sp during the procedure half ofthem with a species other than C albicans However no increasein invasive candidiasis or in deaths related to non-albicans Candidainfections could be observed Very recently van Burik et al79 in alarge randomized double-blind multicentre study on 882 patientsobserved superior efficacy of the echinocandin micafungin (50 mgday) over fluconazole (400 mgday) on the prevention of invasivefungal infection among bone marrow recipients 80 of successversus 73 Further costndashbenefit studies are required to determinewhether micafungin could be an alternative to fluconazole in thatsetting particularly as fluconazole is now generic

Fluconazole for prophylaxis of Candida infections in

neutropenic patients

Neutropenic patients with haematological malignancies are at highrisk for developing invasive and superficial mycoses However allof them do not share the same risk of fungal infection

Prolonged deep neutropenia as observed in intensiveinduction or salvage regimens for acute leukaemia use of corti-costeroids and exposure to high-dose cytosine arabinoside or tomonoclonal antibodies (anti-CD52) are deeply immunosuppress-ing conditions facilitating the emergence of invasive fungalinfections80

Studies versus placebo Seven studies have shown the efficacy offluconazole in the setting of fungal prophylaxis among neutropenicpatients (excluding BMT) including five randomized double-blind placebo-controlled trials81ndash87 Indeed fluconazole hasbeen shown to significantly reduce Candida species colonizationsuperficial infections invasive proven candidal infections as wellas fungal-related mortality A broad range of doses were used inthese studies ranging from 50 to 400 mgday However no benefiton overall mortality has been observed (see Table 7)

Comparative studies Fluconazole has also been compared withother antifungal agents (see Table 8) When compared with oralpolyenes it was at least equivalent in terms of prevention of super-ficial infection except in the study by Rozenberg et al suggestingthat amphotericin B (400 mg middot 4day) might more efficientlyreduce superficial candidal colonization88ndash98 Egger et al88 alsosuggested that fluconazole might reduce the need for curativeamphotericin B among neutropenic patients but taken the absence

of consensus about the use of amphotericin B in the case of per-sistent fever these results are of low clinical pertinence Flucona-zole has an excellent tolerance profile in that population withsimilar efficiency and fewer side effects than intravenous polyeneprophylaxis98

Optimal dose is not clearly defined in neutropenic patientsDosages ranging from 100 to 400 mgday were used with appar-ently the same efficacy Low doses of 50 mgday prevent super-ficial candidiasis but not invasive disease Oral administration wasapparently as efficient as the intravenous one although this pointhad never been extensively studied in appropriate comparativestudies especially as more recent studies allowed either route ofadministration

Recently two meta-analyses reviewed the data extracted fromall major studies on fluconazole prophylaxis in neutropenicpatients with or without BMT99100 Comparators were fungal-related deaths superficial and invasive candidal infections useof parenteral antifungal therapy and infection and colonizationwith fluconazole-resistant species In 2000 Kanda et al reviewed16 controlled studies involving 3734 patients99 Superficial infec-tions were clearly reduced by the use of fluconazole (combined OR023 95 CI 017ndash031) In trials involving neutropenic patientswithout BMT the benefit of fluconazole on invasive infectionsappeared only in studies in which the incidence of fungal infectionwas gt15 with a combined OR at 023 (95CI 015ndash036) Therewas also no difference in the incidence rate of invasive aspergillosisbetween control and study groups Colonization by C krusei wasmore frequent in fluconazole-treated patients (OR 201 95 CI13ndash312) Colonization by C glabrata was more frequent amongpatients with low-dose (50ndash200 mgday) regimen (OR 204 95CI 118ndash353) However there was also no difference between testand control groups in the incidence rate of invasive proven infec-tions with C krusei C glabrata or Aspergillus sp Fungal-relatedmortality was not reduced in fluconazole-treated patients In 2002Bow et al100 similarly reviewed 38 trials including 14 involvingfluconazole (4062 patients with malignant disease and severe neu-tropenia) Fluconazole regimen was associated with benefit onsuperficial and invasive fungal infections and also on fungal infec-tion-related mortality (weighted OR 053 95 CI 034ndash083)Overall mortality was not reduced and no excess of invasiveaspergillosis could be evidenced One negative issue wassubsequently identified in a retrospective study including 3002patients Viscoli et al found that absorbable antifungalprophyl axis in neutropenic patients was associated with anincreased rate of bacteraemia with an estimated OR of 142(95 CI 107ndash188)101

There is no clear international recommendation about the use offluconazole or other antifungal drugs in the non-BMT profoundlyneutropenic setting The IDSA 2002 guidelines for the use ofantimicrobial agents in neutropenic patients with cancer indicatethat lsquoroutine use of fluconazole or itraconazole for all cases ofneutropenia is not recommended However in certain circum-stances in which the frequency of systemic infection due to Calbicans is high and the frequency of systemic infection due toother Candida species and Aspergillus species is low some physi-cians may elect to administer antifungal prophylaxis (D-II)102 InGerman guidelines fluconazole prophylaxis (400 mgday) amongpatients undergoing conventional chemotherapy is a grade C-Irecommendation (poor evidence)103 French guidelines on thecare of invasive candidiasis in adults were recently updatedThe use of fluconazole prophylaxis (400 mgday) is a high

Review

392

Table

7

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

pla

ceb

oo

rn

otr

eatm

ent

inn

eutr

op

enic

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

n

atth

eE

OT

Dea

th

Lav

erd

iere

etal

81

R

DB

PC

M

C

FL

C4

00

mg

day

po

ver

sus

pla

ceb

o

wit

hin

72

h

po

st-i

nit

iati

on

of

chem

oth

erap

y

un

til

PM

N

gt5

00

mm

3

13

5(6

0B

MT

)

13

1(5

8B

MT

)

ND

ND

3

17

Plt0001

31

75

ND

Ro

tste

inet

al

84

R

DB

F

LC

40

0m

gd

ayw

ith

in7

2h

14

1(6

2B

MT

)N

D7

3

015ndash023

ND

PC

M

Cp

ov

ersu

sp

lace

bo

po

st-i

nit

iati

on

of

chem

oth

erap

yu

nti

l

PM

Ngt

50

0m

m3

13

3(5

8B

MT

)18

(P=002)

16

(P=00001)

039ndash030

fungalindex

colonization

(Plt00001)

Ker

net

al

86

R

DB

SC

FL

C4

00

mg

day

po

ver

sus

no

trea

tmen

t

36

32

ND

ND

6

6

ND

no

dif

fere

nce

Sch

affn

eret

al

87

R

DB

PC

S

C

FL

C4

00

mg

day

po

iv

ver

sus

pla

ceb

o

adm

issi

on

un

til

sust

ain

edP

MN

gt5

00

mm

3

75

76

ND

1

12

(P

=0

01

8)

8

C0

F8

9

C5

F4

8

36

(Plt00001)

6

7

Yam

acet

al

85

R

NB

SC

FL

C4

00

mg

day

po

ver

sus

no

D0

chem

oth

erap

y

un

til

PM

N

41

29

ND

ND

9

31

(Plt005)

ND

ND

trea

tmen

tgt

2middot

10

3m

m3

Ch

and

rase

kar

83

R

DB

PC

S

C

FL

C4

00

mg

day

po

ver

sus

pla

ceb

o

D0

chem

oth

erap

yo

r

con

dit

ion

ing

or

reg

imen

un

til

D+

7af

ter

PM

Ngt

10

3m

l

23

(11

BM

T)

24

(11

BM

T)

ND

34

79

(P=

00

00

2)

10

C

0

F

10

5

C5

F0

ND

17

13

Win

sto

n8

2R

D

B

PC

M

C

FL

Cp

o4

00

mg

day

po

iv

ver

sus

pla

ceb

o

D0

chem

oth

erap

y

un

til

PM

Ngt

10

3m

l

12

4

13

2

9

21

(P=

00

2)

6

15

(Plt

00

1)

4

C1

F3

8

C4

5

F

35

29

68

(P=

00

01

)

21

18

R

rand

om

ized

D

B

do

uble

bli

nd

N

B

no

tb

lin

d

PC

p

lace

bo

con

troll

ed

SC

si

ng

lece

ntr

eM

C

mult

icen

tre

FL

C

flu

conaz

ole

p

o

ora

liv

in

trav

eno

us

EO

T

end

of

trea

tmen

tN

D

no

td

on

eC

Candida

sp

F

fila

men

tou

sfu

ng

iP

MN

p

oly

mo

rph

on

ucl

ear

cell

sB

MT

b

on

em

arro

wtr

ansp

lan

tati

on

D

d

ay

Val

ues

giv

enin

bo

ldfa

cear

est

atis

tica

lly

sign

ific

ant

Review

393

Table

8

Co

mp

arat

ive

stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

oth

eran

tifu

ng

als

inn

eutr

op

enic

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

nat

the

EO

TD

eath

Morg

enst

ern

etal

89

R

SB

MC

FL

C1

00

mg

day

po

ver

sus

itra

con

azo

le

25

mg

kg

twic

e

ad

ayp

o

beg

inn

ing

con

dit

ion

ing

reg

imen

un

til

PM

N

gt1

03m

m3gt

1w

eek

22

7

(12

0B

MT

)

21

8

(11

0B

MT

)

ND

5

2

3

C1

F2

1

C1

ND

4

1

Eg

ger

etal

88

R

NB

SC

FL

C4

00

mg

day

ivp

ov

ersu

sn

yst

atin

24middot

10

6U

middot3d

ayp

o

fro

mh

osp

ital

izat

ion

in

iso

lati

on

un

itu

nti

l

end

of

neu

tro

pen

ia

43

(14

BM

T)

46

(19

BM

T)

2

4

0

0

2

4

ND

ND

Bo

dey

etal

98

R

NB

SC

FL

C4

00

mg

day

po

ver

sus

AM

B

05

mg

kgmiddot3

wee

kiv

fro

mD

0ch

emo

ther

apy

un

til

PM

Ngt

10

3m

m3

41

36

4

8

0

0

4

8

18

15

15

9

Ell

iset

al

90

R

DB

SC

FL

Cp

o2

00

mg

day

ver

sus

clo

trim

azo

le

(10

mg

qid

)+

my

cost

atin

50

00

00

IUq

id

adm

issi

on

un

til

PM

Ngt

10

3m

m3

42

(10

BM

T)

48

(13

BM

T)

95

35

(Plt

00

1)

2

13

5

21

ND

19

35

(Plt004)

Men

ich

etti

R

NB

F

LC

15

0m

gd

ayp

oD

-3to

D-1

bef

ore

42

03

5

2

15

N

D1

0

etal

93

MC

ver

sus

AM

B5

00

mg

middot4d

ayp

o

chem

oth

erap

yu

nti

l

PM

Ngt

10

3m

m3

40

05

3

2

1

0

Nin

aneet

al

92

R

NB

MC

chil

dre

n

FL

Cp

o3

mg

kg

day

ver

sus

ny

stat

inp

o

50

00

0U

kg

qid

or

AM

B

25

mg

kg

qid

po

48

hw

ith

inin

itia

tio

n

of

chem

oth

erap

y

un

til

PM

Ngt

10

3m

m3

24

5

25

7

2

8

(P=0002)

1

6

(P=0004)

1

C0

5

F0

5

2

C2

no

dif

fere

nce

inre

du

ctio

n

and

con

tro

lo

f

colo

niz

atio

n

ND

Ak

iyam

a

etal

94

R

NB

SC

FL

C2

00

mg

day

po

ver

sus

AM

B8

00

mg

middot3d

ayp

o

D0

chem

oth

erap

y

un

til

PM

Ngt

50

0m

m3

71

59

ND

ND

1

3

2

9

ND

Ph

ilp

ott

-Ho

war

d

etal

91

R

NB

MC

FL

C5

0m

gd

ayp

ov

ersu

s

AM

B2

gd

ayp

oo

r

ny

stat

in4middot

10

6U

day

bef

ore

chem

oth

erap

y

un

til

PM

Ngt

10

3m

m3

or

4w

eek

s

26

9

26

7

4

12

(P=0001)

2

9

(Plt0001)

2

C1

F1

4

C3

5

F

05

sim

ilar

ND

Meu

nie

ret

al

95

R

NB

SC

FL

Cp

o2

00

mg

day

ver

sus

AM

Bp

o4

30

mg

day

D-2

neu

tro

pen

ia

un

til

PM

Ngt

10

3m

m3

30

(9B

MT

)

29

(9B

MT

)

7

13

0

3

14

C

7

F

7

17

C

10

F7

ND

17

21

Roze

nber

g-A

rska

etal

96

R

NB

SC

FL

C5

0m

gd

ayp

ov

ersu

s

AM

B4

00

mgmiddot4

day

po

D0

neu

tro

pen

ia

un

til

PM

Ngt

50

0m

m3

25

25

ND

0 4

4

C0

F4

4

C4

F0

52

16

ND

Bra

mm

eret

al

97

C

NB

F

LC

50

mg

day

NR

12

62

7

MC

po

ver

sus

ora

l

po

lyen

es

12

24

5

(su

spec

ted

fun

gal

infe

ctio

ns)

ND

ND

ND

ND

Rr

and

om

ized

DB

do

uble

bli

nd

NB

no

tbli

nd

SB

sin

gle

bli

nd

SC

sin

gle

cen

tre

MC

mult

icen

tre

FL

Cf

luco

naz

ole

po

ora

liv

in

trav

eno

us

EO

Te

nd

oftr

eatm

ent

ND

no

tdo

ne

CC

andida

sp

Ff

ilam

ento

us

fun

gi

PM

N

po

lym

orp

ho

nu

clea

rce

lls

BM

T

bo

ne

mar

row

tran

spla

nta

tio

n

D

day

q

id

fou

rti

mes

ad

ay

Val

ues

giv

enin

bo

ldfa

cear

est

atis

tica

lly

sign

ific

ant

Review

394

grade recommendation (A-I) among allogeneic bone marrowrecipients but not in the setting of autologous BMT or acuteleukaemia (httpwwwsrlforgDataDocumentsHTMLO2_refenticls_OA-recommendations20040513asp date last accessed26 December 2005) Thus in the light of the previously describedmeta-analysis fluconazole might be appropriate in neutropenicpatients with a high risk of fungal infection ie those with longduration of neutropenia prolonged corticosteroid therapy butprobably other drugs will be better choices

Fluconazole as prophylaxis for systemic

candidiasis in ICU adults

The extent of the problem There is an increasing incidence of bothbacterial and fungal sepsis occurring in ICU patients A USstudy found that the absolute number of deaths due to invasivemycoses rose from 1557 in 1980 to 6534 in 1997104 Althoughmuch of this increase was associated with fungal infections relatedto HIV there were also marked increases in deaths due to can-didiasis aspergillosis and other mycoses in the non-HIV popula-tion A UK study looking at the outcome of candidaemia infectionsreported 187 episodes of candidaemia per 100 000 finished con-sultant episodes Of them 454 occurred in an ICU setting andC albicans was isolated in 65 of cases105 A Swiss study foundthat two-thirds of episodes of candidaemia occurred in ICU or onsurgical wards with invasive candidiasis occurring 5ndash10 timesmore frequently in an ICU setting than on other wards106

Strikingly in spite of all therapeutic innovations in the field ofantifungal therapy the crude and attributable mortality of nosoco-mial fungaemias have not decreased over the past 15 years(38)107

How are patients at risk of invasive candidiasis identified Thediagnosis of invasive candidiasis may be difficult due to the highfrequency of colonization especially in patients who are on broadspectrum antibiotics A prospective study of non-neutropenicpatients in whom Candida species were isolated found that diges-tive and respiratory samples and the isolation of non-albicansspecies were risk factors for invasive candidiasis108 Additionallythe most significant risk factors for invasive candidaemia identifiedin a surgical ICU in those who had undergone surgery were priorsurgery acute renal failure receipt of total parenteral nutrition andthe presence of a central venous catheter109 This study also foundthat administration of an antifungal agent was associated withdecreased risk for invasive candidal infection For critically illsurgical patients Pittet et al110 proposed a Candida colonizationindex based on the ratio between the number of colonized sites andthe number of sites tested Although its use in hospital practice iscomplex expensive and time-consuming this index was highlypredictive of invasive candidiasis indeed a threshold of 05 ormore correctly identified the infected patients an average of 6days before the documented candidiasis An alternative approachhas been considered using both anti-Candida antibody and antigentitres111 A high concordance between the two has been observedfor patients with invasive candidal disease compared with patientswho were only colonized with Candida Sensitivity and specificityreached 100 and 833 respectively when the two tests werecombined112

Studies that have been done A recent paper has highlighted theimportance of appropriate trial design of antifungal prophylaxisand the need for appropriate assessment of risk factors to identify

those patients who are at higher risk113 Fluconazole has previouslybeen assessed as a prophylactic agent in ITU settings with contra-dictory results

Concerns over a shift inCandida isolates that are less susceptibleor resistant to fluconazole may be balanced against the justificationof using it in appropriately identified high-risk patients114

For Three prospective randomized placebo-controlled trials haveemphasized the efficacy of fluconazole in that setting (see Table 9)In one study 260 critically ill surgical patients staying in ICU forgt3 days mainly pre-hepatic transplantation patients were ran-domly assigned to either placebo or 400 mg of fluconazole perday The risk of fungal infection was reduced by 55 in the flu-conazole group compared with the control group who experienced15 of invasive infections115 In a small study of 43 surgicalpatients with recurrent gastrointestinal leaks or perforations theuse of fluconazole prophylaxis resulted in decreased isolation ofCandida in surveillance cultures and in a decrease in candidalperitonitis 4 versus 35 with a decrease in global invasivecandidiasis (9 versus 35)116 A slightly different approachwas used in a study of 204 critically ill patients in surgical andmedical ICU where fluconazole was used as part of a selectivedigestive decontamination regimen28 These patients appear tomore closely represent a typical group of ICU patients InvasiveCandida infections occurred less frequently in 8 of the flucona-zole group compared with 20 of the placebo group and no shifttowards non-albicans species was observed

Several reviews of historical cohorts have provided similarresults A recent retrospective review in a surgical ICU comparingthe use of fluconazole prophylaxis versus a historical cohort foundthat prophylaxis decreased the incidence of candidaemia and didnot find an increase in non-albicans species117 No reduction ofmortality with fluconazole was observed Secondary Candidainfections in high-risk patients with trauma occurred in 962(145) patients who did not receive fluconazole prophylaxiscompared with 3145 (2) of a historical cohort who did118

In another randomized prospective study of bacterial septicshock fluconazole had a measurable positive impact on survivalalthough no fungal infection was diagnosed This unclear benefi-cial effect might be related to fluconazolersquos observed ability toenhance the bactericidal activity of neutrophils or to prevent Can-dida spp infection which was not diagnosed by standard bloodcultures which are known to be relatively insensitive119120

Against One group of patients at increased risk of invasivecandidiasis includes those who have undergone recent liver trans-plantation In a previously cited prospective study of 35 post-liver-transplantation patients patients with C albicans infectionswere less likely to have received antifungal prophylaxis thanthose with non-albicans Candida infections (136 versus 50P = 004) Non-albicans Candida infections and prior antifungalprophylaxis correlated with poorer outcome49 A further studylooked at 125 critically ill patients who received either fluconazoleprophylaxis or placebo during their entire stay in ICU121 Therewere no significant differences in the incidence of candidal infec-tions nor any difference in the mortality or length of stay on ICU Inthe study performed by Pelz et al115 among pre-liver-transplanta-tion patients no benefit of fluconazole on survival could be noticedalthough a clear reduction of fungal infection was observed

There are however concerns that the use of prophylacticfluconazole in critical care patients favours the emergence of

Review

395

Table

6

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

oth

eran

tifu

ng

als

inal

log

enei

can

dau

tolo

go

us

bo

ne

mar

row

tran

spla

nt

pat

ien

ts

Ref

eren

ceS

tud

yd

esig

nR

egim

enD

ura

tio

no

ftr

eatm

ent

Nu

mb

ero

f

pat

ien

ts

(au

to)

Su

per

fici

al

Candida

sp

infe

ctio

ns

Inv

asiv

e

fun

gal

infe

ctio

ns

Candida

sp

colo

niz

atio

n

atth

eE

OT

Dea

th

rela

ted

toIF

I

Ov

eral

l

dea

th

van

Bu

riket

al

79

R

DB

M

CF

LC

po

40

0m

gd

ay

ver

sus

mic

afu

ng

in

(50

mg

day

)

48

hb

efo

reco

nd

itio

nin

g

reg

imen

un

til

eng

raft

men

t

45

7(2

01

)

42

5(2

03

)

ND

24

C

04

F2

16

C

09

F1

7

34

52

lt1

lt1

6

4

Mar

ret

al

76

R

NB

S

CF

LC

po

or

iv

40

0m

gd

ayv

ersu

s

itra

con

azo

le

75

mg

kg

po

20

0m

gd

ay

con

dit

ion

ing

reg

imen

toD

-12

0(n

=1

87

)

D-0

toD

-12

0(n

=1

02

)

14

8

15

1

ND

19

C

3

F1

6

18

C

3

F

15

ND

7

8

31

39

Win

sto

net

al

75

R

NB

M

CF

LC

po

or

iv4

00

mg

day

ver

sus

itra

con

azo

le

iv2

00

mg

day

or

po

25

mg

kg

day

middot3d

ay

D-1

toD

-10

0

afte

rB

MT

68

72

3

4

25

9

(P=001)

ND

ND

42

45

Ko

het

al

22

7R

N

B

SC

FL

Cp

o2

00

mg

day

ver

sus

amp

ho

teri

cin

B

iv0

2m

gk

gd

ay

24

hb

efo

reco

nd

itio

nin

g

reg

imen

un

til

eng

raft

men

t

(PM

Ngt

50

0m

m3gt

3d

ays)

10

0(2

6)

86

(20

)

1

5

12

13

ND

6

7

22

30

Wo

lffet

al

73

R

NB

M

CF

LC

po

40

0m

gd

ay

ver

sus

amp

ho

teri

cin

B

iv0

2m

gk

gd

ay

D-1

pre

con

dit

ion

ing

reg

imen

un

til

eng

raft

men

t

(PM

Ngt

50

0m

m3)

19

6(1

42

)

15

9(1

10

)

ND

26

2

27

43

3

1

12

12

An

nal

oro

etal

74

R

NB

S

CF

LC

po

30

0m

gd

ay

ver

sus

FL

Cp

o

50

mg

day

ver

sus

itra

con

azo

le4

00

mg

day

D-1

pre

con

dit

ion

ing

reg

imen

un

til

eng

raft

men

t

(PM

Ngt

50

0m

m3)

28

30

31

ND

4

3

13

ND

no

dif

fere

nce

ND

Glu

ckm

anet

al

22

8R

N

B

SC

FL

Cp

oi

v

10

0m

gd

ay

ver

sus

ket

oco

naz

ole

40

0m

gd

ay

Dndash

8to

D+

90

afte

rB

MT

30

29

3

11

10

7

47

41

ND

ND

Rra

ndom

ized

D

Bdouble

bli

nd

NB

not

bli

nd

PC

pla

cebo

contr

oll

ed

SC

si

ngle

centr

eM

Cm

ult

icen

tre

FL

Cfl

uco

naz

ole

poora

liv

in

trav

eno

us

EO

Ten

do

ftr

eatm

ent

ND

n

ot

do

ne

CCandida

sp

F

fila

men

tous

fungi

PM

N

poly

morp

honucl

ear

cell

sB

MT

bone

mar

row

tran

spla

nta

tion

D

day

V

alues

giv

enin

bold

face

are

stat

isti

call

ysi

gnif

ican

t

Review

391

limited to yeasts fluconazole has been widely adopted as an effec-tive and safe therapy Its use is now recommended from the day ofhaematopoietic stem cell transplantation until engraftment inguidelines for prevention of opportunistic infections among allo-geneic bone marrow recipients67 The optimal dose of fluconazolein that setting is not clearly determined The posology of 400 mgday is recommended by the IDSA However lower doses have beenshown to be similarly effective in reducing the risk of invasiveinfections and candidal colonization7176 MacMillan et al77 in alarge cohort of 253 patients demonstrated similar efficiency of highand low dosages of fluconazole (200 and 400 mgday) on the rate offungal colonization and infection No increase of reduced suscep-tibility in isolates of Candida was seen at the low doses Theadoption of fluconazole as prophylactic regimen in BMT has raisedconcern about a shift of colonization towards azole-resistant strainsof Candida sp Indeed Marr et al78 observed that out of 585patients undergoing BMT with prophylactic fluconazole 44were colonized with Candida sp during the procedure half ofthem with a species other than C albicans However no increasein invasive candidiasis or in deaths related to non-albicans Candidainfections could be observed Very recently van Burik et al79 in alarge randomized double-blind multicentre study on 882 patientsobserved superior efficacy of the echinocandin micafungin (50 mgday) over fluconazole (400 mgday) on the prevention of invasivefungal infection among bone marrow recipients 80 of successversus 73 Further costndashbenefit studies are required to determinewhether micafungin could be an alternative to fluconazole in thatsetting particularly as fluconazole is now generic

Fluconazole for prophylaxis of Candida infections in

neutropenic patients

Neutropenic patients with haematological malignancies are at highrisk for developing invasive and superficial mycoses However allof them do not share the same risk of fungal infection

Prolonged deep neutropenia as observed in intensiveinduction or salvage regimens for acute leukaemia use of corti-costeroids and exposure to high-dose cytosine arabinoside or tomonoclonal antibodies (anti-CD52) are deeply immunosuppress-ing conditions facilitating the emergence of invasive fungalinfections80

Studies versus placebo Seven studies have shown the efficacy offluconazole in the setting of fungal prophylaxis among neutropenicpatients (excluding BMT) including five randomized double-blind placebo-controlled trials81ndash87 Indeed fluconazole hasbeen shown to significantly reduce Candida species colonizationsuperficial infections invasive proven candidal infections as wellas fungal-related mortality A broad range of doses were used inthese studies ranging from 50 to 400 mgday However no benefiton overall mortality has been observed (see Table 7)

Comparative studies Fluconazole has also been compared withother antifungal agents (see Table 8) When compared with oralpolyenes it was at least equivalent in terms of prevention of super-ficial infection except in the study by Rozenberg et al suggestingthat amphotericin B (400 mg middot 4day) might more efficientlyreduce superficial candidal colonization88ndash98 Egger et al88 alsosuggested that fluconazole might reduce the need for curativeamphotericin B among neutropenic patients but taken the absence

of consensus about the use of amphotericin B in the case of per-sistent fever these results are of low clinical pertinence Flucona-zole has an excellent tolerance profile in that population withsimilar efficiency and fewer side effects than intravenous polyeneprophylaxis98

Optimal dose is not clearly defined in neutropenic patientsDosages ranging from 100 to 400 mgday were used with appar-ently the same efficacy Low doses of 50 mgday prevent super-ficial candidiasis but not invasive disease Oral administration wasapparently as efficient as the intravenous one although this pointhad never been extensively studied in appropriate comparativestudies especially as more recent studies allowed either route ofadministration

Recently two meta-analyses reviewed the data extracted fromall major studies on fluconazole prophylaxis in neutropenicpatients with or without BMT99100 Comparators were fungal-related deaths superficial and invasive candidal infections useof parenteral antifungal therapy and infection and colonizationwith fluconazole-resistant species In 2000 Kanda et al reviewed16 controlled studies involving 3734 patients99 Superficial infec-tions were clearly reduced by the use of fluconazole (combined OR023 95 CI 017ndash031) In trials involving neutropenic patientswithout BMT the benefit of fluconazole on invasive infectionsappeared only in studies in which the incidence of fungal infectionwas gt15 with a combined OR at 023 (95CI 015ndash036) Therewas also no difference in the incidence rate of invasive aspergillosisbetween control and study groups Colonization by C krusei wasmore frequent in fluconazole-treated patients (OR 201 95 CI13ndash312) Colonization by C glabrata was more frequent amongpatients with low-dose (50ndash200 mgday) regimen (OR 204 95CI 118ndash353) However there was also no difference between testand control groups in the incidence rate of invasive proven infec-tions with C krusei C glabrata or Aspergillus sp Fungal-relatedmortality was not reduced in fluconazole-treated patients In 2002Bow et al100 similarly reviewed 38 trials including 14 involvingfluconazole (4062 patients with malignant disease and severe neu-tropenia) Fluconazole regimen was associated with benefit onsuperficial and invasive fungal infections and also on fungal infec-tion-related mortality (weighted OR 053 95 CI 034ndash083)Overall mortality was not reduced and no excess of invasiveaspergillosis could be evidenced One negative issue wassubsequently identified in a retrospective study including 3002patients Viscoli et al found that absorbable antifungalprophyl axis in neutropenic patients was associated with anincreased rate of bacteraemia with an estimated OR of 142(95 CI 107ndash188)101

There is no clear international recommendation about the use offluconazole or other antifungal drugs in the non-BMT profoundlyneutropenic setting The IDSA 2002 guidelines for the use ofantimicrobial agents in neutropenic patients with cancer indicatethat lsquoroutine use of fluconazole or itraconazole for all cases ofneutropenia is not recommended However in certain circum-stances in which the frequency of systemic infection due to Calbicans is high and the frequency of systemic infection due toother Candida species and Aspergillus species is low some physi-cians may elect to administer antifungal prophylaxis (D-II)102 InGerman guidelines fluconazole prophylaxis (400 mgday) amongpatients undergoing conventional chemotherapy is a grade C-Irecommendation (poor evidence)103 French guidelines on thecare of invasive candidiasis in adults were recently updatedThe use of fluconazole prophylaxis (400 mgday) is a high

Review

392

Table

7

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

pla

ceb

oo

rn

otr

eatm

ent

inn

eutr

op

enic

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

n

atth

eE

OT

Dea

th

Lav

erd

iere

etal

81

R

DB

PC

M

C

FL

C4

00

mg

day

po

ver

sus

pla

ceb

o

wit

hin

72

h

po

st-i

nit

iati

on

of

chem

oth

erap

y

un

til

PM

N

gt5

00

mm

3

13

5(6

0B

MT

)

13

1(5

8B

MT

)

ND

ND

3

17

Plt0001

31

75

ND

Ro

tste

inet

al

84

R

DB

F

LC

40

0m

gd

ayw

ith

in7

2h

14

1(6

2B

MT

)N

D7

3

015ndash023

ND

PC

M

Cp

ov

ersu

sp

lace

bo

po

st-i

nit

iati

on

of

chem

oth

erap

yu

nti

l

PM

Ngt

50

0m

m3

13

3(5

8B

MT

)18

(P=002)

16

(P=00001)

039ndash030

fungalindex

colonization

(Plt00001)

Ker

net

al

86

R

DB

SC

FL

C4

00

mg

day

po

ver

sus

no

trea

tmen

t

36

32

ND

ND

6

6

ND

no

dif

fere

nce

Sch

affn

eret

al

87

R

DB

PC

S

C

FL

C4

00

mg

day

po

iv

ver

sus

pla

ceb

o

adm

issi

on

un

til

sust

ain

edP

MN

gt5

00

mm

3

75

76

ND

1

12

(P

=0

01

8)

8

C0

F8

9

C5

F4

8

36

(Plt00001)

6

7

Yam

acet

al

85

R

NB

SC

FL

C4

00

mg

day

po

ver

sus

no

D0

chem

oth

erap

y

un

til

PM

N

41

29

ND

ND

9

31

(Plt005)

ND

ND

trea

tmen

tgt

2middot

10

3m

m3

Ch

and

rase

kar

83

R

DB

PC

S

C

FL

C4

00

mg

day

po

ver

sus

pla

ceb

o

D0

chem

oth

erap

yo

r

con

dit

ion

ing

or

reg

imen

un

til

D+

7af

ter

PM

Ngt

10

3m

l

23

(11

BM

T)

24

(11

BM

T)

ND

34

79

(P=

00

00

2)

10

C

0

F

10

5

C5

F0

ND

17

13

Win

sto

n8

2R

D

B

PC

M

C

FL

Cp

o4

00

mg

day

po

iv

ver

sus

pla

ceb

o

D0

chem

oth

erap

y

un

til

PM

Ngt

10

3m

l

12

4

13

2

9

21

(P=

00

2)

6

15

(Plt

00

1)

4

C1

F3

8

C4

5

F

35

29

68

(P=

00

01

)

21

18

R

rand

om

ized

D

B

do

uble

bli

nd

N

B

no

tb

lin

d

PC

p

lace

bo

con

troll

ed

SC

si

ng

lece

ntr

eM

C

mult

icen

tre

FL

C

flu

conaz

ole

p

o

ora

liv

in

trav

eno

us

EO

T

end

of

trea

tmen

tN

D

no

td

on

eC

Candida

sp

F

fila

men

tou

sfu

ng

iP

MN

p

oly

mo

rph

on

ucl

ear

cell

sB

MT

b

on

em

arro

wtr

ansp

lan

tati

on

D

d

ay

Val

ues

giv

enin

bo

ldfa

cear

est

atis

tica

lly

sign

ific

ant

Review

393

Table

8

Co

mp

arat

ive

stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

oth

eran

tifu

ng

als

inn

eutr

op

enic

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

nat

the

EO

TD

eath

Morg

enst

ern

etal

89

R

SB

MC

FL

C1

00

mg

day

po

ver

sus

itra

con

azo

le

25

mg

kg

twic

e

ad

ayp

o

beg

inn

ing

con

dit

ion

ing

reg

imen

un

til

PM

N

gt1

03m

m3gt

1w

eek

22

7

(12

0B

MT

)

21

8

(11

0B

MT

)

ND

5

2

3

C1

F2

1

C1

ND

4

1

Eg

ger

etal

88

R

NB

SC

FL

C4

00

mg

day

ivp

ov

ersu

sn

yst

atin

24middot

10

6U

middot3d

ayp

o

fro

mh

osp

ital

izat

ion

in

iso

lati

on

un

itu

nti

l

end

of

neu

tro

pen

ia

43

(14

BM

T)

46

(19

BM

T)

2

4

0

0

2

4

ND

ND

Bo

dey

etal

98

R

NB

SC

FL

C4

00

mg

day

po

ver

sus

AM

B

05

mg

kgmiddot3

wee

kiv

fro

mD

0ch

emo

ther

apy

un

til

PM

Ngt

10

3m

m3

41

36

4

8

0

0

4

8

18

15

15

9

Ell

iset

al

90

R

DB

SC

FL

Cp

o2

00

mg

day

ver

sus

clo

trim

azo

le

(10

mg

qid

)+

my

cost

atin

50

00

00

IUq

id

adm

issi

on

un

til

PM

Ngt

10

3m

m3

42

(10

BM

T)

48

(13

BM

T)

95

35

(Plt

00

1)

2

13

5

21

ND

19

35

(Plt004)

Men

ich

etti

R

NB

F

LC

15

0m

gd

ayp

oD

-3to

D-1

bef

ore

42

03

5

2

15

N

D1

0

etal

93

MC

ver

sus

AM

B5

00

mg

middot4d

ayp

o

chem

oth

erap

yu

nti

l

PM

Ngt

10

3m

m3

40

05

3

2

1

0

Nin

aneet

al

92

R

NB

MC

chil

dre

n

FL

Cp

o3

mg

kg

day

ver

sus

ny

stat

inp

o

50

00

0U

kg

qid

or

AM

B

25

mg

kg

qid

po

48

hw

ith

inin

itia

tio

n

of

chem

oth

erap

y

un

til

PM

Ngt

10

3m

m3

24

5

25

7

2

8

(P=0002)

1

6

(P=0004)

1

C0

5

F0

5

2

C2

no

dif

fere

nce

inre

du

ctio

n

and

con

tro

lo

f

colo

niz

atio

n

ND

Ak

iyam

a

etal

94

R

NB

SC

FL

C2

00

mg

day

po

ver

sus

AM

B8

00

mg

middot3d

ayp

o

D0

chem

oth

erap

y

un

til

PM

Ngt

50

0m

m3

71

59

ND

ND

1

3

2

9

ND

Ph

ilp

ott

-Ho

war

d

etal

91

R

NB

MC

FL

C5

0m

gd

ayp

ov

ersu

s

AM

B2

gd

ayp

oo

r

ny

stat

in4middot

10

6U

day

bef

ore

chem

oth

erap

y

un

til

PM

Ngt

10

3m

m3

or

4w

eek

s

26

9

26

7

4

12

(P=0001)

2

9

(Plt0001)

2

C1

F1

4

C3

5

F

05

sim

ilar

ND

Meu

nie

ret

al

95

R

NB

SC

FL

Cp

o2

00

mg

day

ver

sus

AM

Bp

o4

30

mg

day

D-2

neu

tro

pen

ia

un

til

PM

Ngt

10

3m

m3

30

(9B

MT

)

29

(9B

MT

)

7

13

0

3

14

C

7

F

7

17

C

10

F7

ND

17

21

Roze

nber

g-A

rska

etal

96

R

NB

SC

FL

C5

0m

gd

ayp

ov

ersu

s

AM

B4

00

mgmiddot4

day

po

D0

neu

tro

pen

ia

un

til

PM

Ngt

50

0m

m3

25

25

ND

0 4

4

C0

F4

4

C4

F0

52

16

ND

Bra

mm

eret

al

97

C

NB

F

LC

50

mg

day

NR

12

62

7

MC

po

ver

sus

ora

l

po

lyen

es

12

24

5

(su

spec

ted

fun

gal

infe

ctio

ns)

ND

ND

ND

ND

Rr

and

om

ized

DB

do

uble

bli

nd

NB

no

tbli

nd

SB

sin

gle

bli

nd

SC

sin

gle

cen

tre

MC

mult

icen

tre

FL

Cf

luco

naz

ole

po

ora

liv

in

trav

eno

us

EO

Te

nd

oftr

eatm

ent

ND

no

tdo

ne

CC

andida

sp

Ff

ilam

ento

us

fun

gi

PM

N

po

lym

orp

ho

nu

clea

rce

lls

BM

T

bo

ne

mar

row

tran

spla

nta

tio

n

D

day

q

id

fou

rti

mes

ad

ay

Val

ues

giv

enin

bo

ldfa

cear

est

atis

tica

lly

sign

ific

ant

Review

394

grade recommendation (A-I) among allogeneic bone marrowrecipients but not in the setting of autologous BMT or acuteleukaemia (httpwwwsrlforgDataDocumentsHTMLO2_refenticls_OA-recommendations20040513asp date last accessed26 December 2005) Thus in the light of the previously describedmeta-analysis fluconazole might be appropriate in neutropenicpatients with a high risk of fungal infection ie those with longduration of neutropenia prolonged corticosteroid therapy butprobably other drugs will be better choices

Fluconazole as prophylaxis for systemic

candidiasis in ICU adults

The extent of the problem There is an increasing incidence of bothbacterial and fungal sepsis occurring in ICU patients A USstudy found that the absolute number of deaths due to invasivemycoses rose from 1557 in 1980 to 6534 in 1997104 Althoughmuch of this increase was associated with fungal infections relatedto HIV there were also marked increases in deaths due to can-didiasis aspergillosis and other mycoses in the non-HIV popula-tion A UK study looking at the outcome of candidaemia infectionsreported 187 episodes of candidaemia per 100 000 finished con-sultant episodes Of them 454 occurred in an ICU setting andC albicans was isolated in 65 of cases105 A Swiss study foundthat two-thirds of episodes of candidaemia occurred in ICU or onsurgical wards with invasive candidiasis occurring 5ndash10 timesmore frequently in an ICU setting than on other wards106

Strikingly in spite of all therapeutic innovations in the field ofantifungal therapy the crude and attributable mortality of nosoco-mial fungaemias have not decreased over the past 15 years(38)107

How are patients at risk of invasive candidiasis identified Thediagnosis of invasive candidiasis may be difficult due to the highfrequency of colonization especially in patients who are on broadspectrum antibiotics A prospective study of non-neutropenicpatients in whom Candida species were isolated found that diges-tive and respiratory samples and the isolation of non-albicansspecies were risk factors for invasive candidiasis108 Additionallythe most significant risk factors for invasive candidaemia identifiedin a surgical ICU in those who had undergone surgery were priorsurgery acute renal failure receipt of total parenteral nutrition andthe presence of a central venous catheter109 This study also foundthat administration of an antifungal agent was associated withdecreased risk for invasive candidal infection For critically illsurgical patients Pittet et al110 proposed a Candida colonizationindex based on the ratio between the number of colonized sites andthe number of sites tested Although its use in hospital practice iscomplex expensive and time-consuming this index was highlypredictive of invasive candidiasis indeed a threshold of 05 ormore correctly identified the infected patients an average of 6days before the documented candidiasis An alternative approachhas been considered using both anti-Candida antibody and antigentitres111 A high concordance between the two has been observedfor patients with invasive candidal disease compared with patientswho were only colonized with Candida Sensitivity and specificityreached 100 and 833 respectively when the two tests werecombined112

Studies that have been done A recent paper has highlighted theimportance of appropriate trial design of antifungal prophylaxisand the need for appropriate assessment of risk factors to identify

those patients who are at higher risk113 Fluconazole has previouslybeen assessed as a prophylactic agent in ITU settings with contra-dictory results

Concerns over a shift inCandida isolates that are less susceptibleor resistant to fluconazole may be balanced against the justificationof using it in appropriately identified high-risk patients114

For Three prospective randomized placebo-controlled trials haveemphasized the efficacy of fluconazole in that setting (see Table 9)In one study 260 critically ill surgical patients staying in ICU forgt3 days mainly pre-hepatic transplantation patients were ran-domly assigned to either placebo or 400 mg of fluconazole perday The risk of fungal infection was reduced by 55 in the flu-conazole group compared with the control group who experienced15 of invasive infections115 In a small study of 43 surgicalpatients with recurrent gastrointestinal leaks or perforations theuse of fluconazole prophylaxis resulted in decreased isolation ofCandida in surveillance cultures and in a decrease in candidalperitonitis 4 versus 35 with a decrease in global invasivecandidiasis (9 versus 35)116 A slightly different approachwas used in a study of 204 critically ill patients in surgical andmedical ICU where fluconazole was used as part of a selectivedigestive decontamination regimen28 These patients appear tomore closely represent a typical group of ICU patients InvasiveCandida infections occurred less frequently in 8 of the flucona-zole group compared with 20 of the placebo group and no shifttowards non-albicans species was observed

Several reviews of historical cohorts have provided similarresults A recent retrospective review in a surgical ICU comparingthe use of fluconazole prophylaxis versus a historical cohort foundthat prophylaxis decreased the incidence of candidaemia and didnot find an increase in non-albicans species117 No reduction ofmortality with fluconazole was observed Secondary Candidainfections in high-risk patients with trauma occurred in 962(145) patients who did not receive fluconazole prophylaxiscompared with 3145 (2) of a historical cohort who did118

In another randomized prospective study of bacterial septicshock fluconazole had a measurable positive impact on survivalalthough no fungal infection was diagnosed This unclear benefi-cial effect might be related to fluconazolersquos observed ability toenhance the bactericidal activity of neutrophils or to prevent Can-dida spp infection which was not diagnosed by standard bloodcultures which are known to be relatively insensitive119120

Against One group of patients at increased risk of invasivecandidiasis includes those who have undergone recent liver trans-plantation In a previously cited prospective study of 35 post-liver-transplantation patients patients with C albicans infectionswere less likely to have received antifungal prophylaxis thanthose with non-albicans Candida infections (136 versus 50P = 004) Non-albicans Candida infections and prior antifungalprophylaxis correlated with poorer outcome49 A further studylooked at 125 critically ill patients who received either fluconazoleprophylaxis or placebo during their entire stay in ICU121 Therewere no significant differences in the incidence of candidal infec-tions nor any difference in the mortality or length of stay on ICU Inthe study performed by Pelz et al115 among pre-liver-transplanta-tion patients no benefit of fluconazole on survival could be noticedalthough a clear reduction of fungal infection was observed

There are however concerns that the use of prophylacticfluconazole in critical care patients favours the emergence of

Review

395

limited to yeasts fluconazole has been widely adopted as an effec-tive and safe therapy Its use is now recommended from the day ofhaematopoietic stem cell transplantation until engraftment inguidelines for prevention of opportunistic infections among allo-geneic bone marrow recipients67 The optimal dose of fluconazolein that setting is not clearly determined The posology of 400 mgday is recommended by the IDSA However lower doses have beenshown to be similarly effective in reducing the risk of invasiveinfections and candidal colonization7176 MacMillan et al77 in alarge cohort of 253 patients demonstrated similar efficiency of highand low dosages of fluconazole (200 and 400 mgday) on the rate offungal colonization and infection No increase of reduced suscep-tibility in isolates of Candida was seen at the low doses Theadoption of fluconazole as prophylactic regimen in BMT has raisedconcern about a shift of colonization towards azole-resistant strainsof Candida sp Indeed Marr et al78 observed that out of 585patients undergoing BMT with prophylactic fluconazole 44were colonized with Candida sp during the procedure half ofthem with a species other than C albicans However no increasein invasive candidiasis or in deaths related to non-albicans Candidainfections could be observed Very recently van Burik et al79 in alarge randomized double-blind multicentre study on 882 patientsobserved superior efficacy of the echinocandin micafungin (50 mgday) over fluconazole (400 mgday) on the prevention of invasivefungal infection among bone marrow recipients 80 of successversus 73 Further costndashbenefit studies are required to determinewhether micafungin could be an alternative to fluconazole in thatsetting particularly as fluconazole is now generic

Fluconazole for prophylaxis of Candida infections in

neutropenic patients

Neutropenic patients with haematological malignancies are at highrisk for developing invasive and superficial mycoses However allof them do not share the same risk of fungal infection

Prolonged deep neutropenia as observed in intensiveinduction or salvage regimens for acute leukaemia use of corti-costeroids and exposure to high-dose cytosine arabinoside or tomonoclonal antibodies (anti-CD52) are deeply immunosuppress-ing conditions facilitating the emergence of invasive fungalinfections80

Studies versus placebo Seven studies have shown the efficacy offluconazole in the setting of fungal prophylaxis among neutropenicpatients (excluding BMT) including five randomized double-blind placebo-controlled trials81ndash87 Indeed fluconazole hasbeen shown to significantly reduce Candida species colonizationsuperficial infections invasive proven candidal infections as wellas fungal-related mortality A broad range of doses were used inthese studies ranging from 50 to 400 mgday However no benefiton overall mortality has been observed (see Table 7)

Comparative studies Fluconazole has also been compared withother antifungal agents (see Table 8) When compared with oralpolyenes it was at least equivalent in terms of prevention of super-ficial infection except in the study by Rozenberg et al suggestingthat amphotericin B (400 mg middot 4day) might more efficientlyreduce superficial candidal colonization88ndash98 Egger et al88 alsosuggested that fluconazole might reduce the need for curativeamphotericin B among neutropenic patients but taken the absence

of consensus about the use of amphotericin B in the case of per-sistent fever these results are of low clinical pertinence Flucona-zole has an excellent tolerance profile in that population withsimilar efficiency and fewer side effects than intravenous polyeneprophylaxis98

Optimal dose is not clearly defined in neutropenic patientsDosages ranging from 100 to 400 mgday were used with appar-ently the same efficacy Low doses of 50 mgday prevent super-ficial candidiasis but not invasive disease Oral administration wasapparently as efficient as the intravenous one although this pointhad never been extensively studied in appropriate comparativestudies especially as more recent studies allowed either route ofadministration

Recently two meta-analyses reviewed the data extracted fromall major studies on fluconazole prophylaxis in neutropenicpatients with or without BMT99100 Comparators were fungal-related deaths superficial and invasive candidal infections useof parenteral antifungal therapy and infection and colonizationwith fluconazole-resistant species In 2000 Kanda et al reviewed16 controlled studies involving 3734 patients99 Superficial infec-tions were clearly reduced by the use of fluconazole (combined OR023 95 CI 017ndash031) In trials involving neutropenic patientswithout BMT the benefit of fluconazole on invasive infectionsappeared only in studies in which the incidence of fungal infectionwas gt15 with a combined OR at 023 (95CI 015ndash036) Therewas also no difference in the incidence rate of invasive aspergillosisbetween control and study groups Colonization by C krusei wasmore frequent in fluconazole-treated patients (OR 201 95 CI13ndash312) Colonization by C glabrata was more frequent amongpatients with low-dose (50ndash200 mgday) regimen (OR 204 95CI 118ndash353) However there was also no difference between testand control groups in the incidence rate of invasive proven infec-tions with C krusei C glabrata or Aspergillus sp Fungal-relatedmortality was not reduced in fluconazole-treated patients In 2002Bow et al100 similarly reviewed 38 trials including 14 involvingfluconazole (4062 patients with malignant disease and severe neu-tropenia) Fluconazole regimen was associated with benefit onsuperficial and invasive fungal infections and also on fungal infec-tion-related mortality (weighted OR 053 95 CI 034ndash083)Overall mortality was not reduced and no excess of invasiveaspergillosis could be evidenced One negative issue wassubsequently identified in a retrospective study including 3002patients Viscoli et al found that absorbable antifungalprophyl axis in neutropenic patients was associated with anincreased rate of bacteraemia with an estimated OR of 142(95 CI 107ndash188)101

There is no clear international recommendation about the use offluconazole or other antifungal drugs in the non-BMT profoundlyneutropenic setting The IDSA 2002 guidelines for the use ofantimicrobial agents in neutropenic patients with cancer indicatethat lsquoroutine use of fluconazole or itraconazole for all cases ofneutropenia is not recommended However in certain circum-stances in which the frequency of systemic infection due to Calbicans is high and the frequency of systemic infection due toother Candida species and Aspergillus species is low some physi-cians may elect to administer antifungal prophylaxis (D-II)102 InGerman guidelines fluconazole prophylaxis (400 mgday) amongpatients undergoing conventional chemotherapy is a grade C-Irecommendation (poor evidence)103 French guidelines on thecare of invasive candidiasis in adults were recently updatedThe use of fluconazole prophylaxis (400 mgday) is a high

Review

392

Table

7

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

pla

ceb

oo

rn

otr

eatm

ent

inn

eutr

op

enic

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

n

atth

eE

OT

Dea

th

Lav

erd

iere

etal

81

R

DB

PC

M

C

FL

C4

00

mg

day

po

ver

sus

pla

ceb

o

wit

hin

72

h

po

st-i

nit

iati

on

of

chem

oth

erap

y

un

til

PM

N

gt5

00

mm

3

13

5(6

0B

MT

)

13

1(5

8B

MT

)

ND

ND

3

17

Plt0001

31

75

ND

Ro

tste

inet

al

84

R

DB

F

LC

40

0m

gd

ayw

ith

in7

2h

14

1(6

2B

MT

)N

D7

3

015ndash023

ND

PC

M

Cp

ov

ersu

sp

lace

bo

po

st-i

nit

iati

on

of

chem

oth

erap

yu

nti

l

PM

Ngt

50

0m

m3

13

3(5

8B

MT

)18

(P=002)

16

(P=00001)

039ndash030

fungalindex

colonization

(Plt00001)

Ker

net

al

86

R

DB

SC

FL

C4

00

mg

day

po

ver

sus

no

trea

tmen

t

36

32

ND

ND

6

6

ND

no

dif

fere

nce

Sch

affn

eret

al

87

R

DB

PC

S

C

FL

C4

00

mg

day

po

iv

ver

sus

pla

ceb

o

adm

issi

on

un

til

sust

ain

edP

MN

gt5

00

mm

3

75

76

ND

1

12

(P

=0

01

8)

8

C0

F8

9

C5

F4

8

36

(Plt00001)

6

7

Yam

acet

al

85

R

NB

SC

FL

C4

00

mg

day

po

ver

sus

no

D0

chem

oth

erap

y

un

til

PM

N

41

29

ND

ND

9

31

(Plt005)

ND

ND

trea

tmen

tgt

2middot

10

3m

m3

Ch

and

rase

kar

83

R

DB

PC

S

C

FL

C4

00

mg

day

po

ver

sus

pla

ceb

o

D0

chem

oth

erap

yo

r

con

dit

ion

ing

or

reg

imen

un

til

D+

7af

ter

PM

Ngt

10

3m

l

23

(11

BM

T)

24

(11

BM

T)

ND

34

79

(P=

00

00

2)

10

C

0

F

10

5

C5

F0

ND

17

13

Win

sto

n8

2R

D

B

PC

M

C

FL

Cp

o4

00

mg

day

po

iv

ver

sus

pla

ceb

o

D0

chem

oth

erap

y

un

til

PM

Ngt

10

3m

l

12

4

13

2

9

21

(P=

00

2)

6

15

(Plt

00

1)

4

C1

F3

8

C4

5

F

35

29

68

(P=

00

01

)

21

18

R

rand

om

ized

D

B

do

uble

bli

nd

N

B

no

tb

lin

d

PC

p

lace

bo

con

troll

ed

SC

si

ng

lece

ntr

eM

C

mult

icen

tre

FL

C

flu

conaz

ole

p

o

ora

liv

in

trav

eno

us

EO

T

end

of

trea

tmen

tN

D

no

td

on

eC

Candida

sp

F

fila

men

tou

sfu

ng

iP

MN

p

oly

mo

rph

on

ucl

ear

cell

sB

MT

b

on

em

arro

wtr

ansp

lan

tati

on

D

d

ay

Val

ues

giv

enin

bo

ldfa

cear

est

atis

tica

lly

sign

ific

ant

Review

393

Table

8

Co

mp

arat

ive

stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

oth

eran

tifu

ng

als

inn

eutr

op

enic

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

nat

the

EO

TD

eath

Morg

enst

ern

etal

89

R

SB

MC

FL

C1

00

mg

day

po

ver

sus

itra

con

azo

le

25

mg

kg

twic

e

ad

ayp

o

beg

inn

ing

con

dit

ion

ing

reg

imen

un

til

PM

N

gt1

03m

m3gt

1w

eek

22

7

(12

0B

MT

)

21

8

(11

0B

MT

)

ND

5

2

3

C1

F2

1

C1

ND

4

1

Eg

ger

etal

88

R

NB

SC

FL

C4

00

mg

day

ivp

ov

ersu

sn

yst

atin

24middot

10

6U

middot3d

ayp

o

fro

mh

osp

ital

izat

ion

in

iso

lati

on

un

itu

nti

l

end

of

neu

tro

pen

ia

43

(14

BM

T)

46

(19

BM

T)

2

4

0

0

2

4

ND

ND

Bo

dey

etal

98

R

NB

SC

FL

C4

00

mg

day

po

ver

sus

AM

B

05

mg

kgmiddot3

wee

kiv

fro

mD

0ch

emo

ther

apy

un

til

PM

Ngt

10

3m

m3

41

36

4

8

0

0

4

8

18

15

15

9

Ell

iset

al

90

R

DB

SC

FL

Cp

o2

00

mg

day

ver

sus

clo

trim

azo

le

(10

mg

qid

)+

my

cost

atin

50

00

00

IUq

id

adm

issi

on

un

til

PM

Ngt

10

3m

m3

42

(10

BM

T)

48

(13

BM

T)

95

35

(Plt

00

1)

2

13

5

21

ND

19

35

(Plt004)

Men

ich

etti

R

NB

F

LC

15

0m

gd

ayp

oD

-3to

D-1

bef

ore

42

03

5

2

15

N

D1

0

etal

93

MC

ver

sus

AM

B5

00

mg

middot4d

ayp

o

chem

oth

erap

yu

nti

l

PM

Ngt

10

3m

m3

40

05

3

2

1

0

Nin

aneet

al

92

R

NB

MC

chil

dre

n

FL

Cp

o3

mg

kg

day

ver

sus

ny

stat

inp

o

50

00

0U

kg

qid

or

AM

B

25

mg

kg

qid

po

48

hw

ith

inin

itia

tio

n

of

chem

oth

erap

y

un

til

PM

Ngt

10

3m

m3

24

5

25

7

2

8

(P=0002)

1

6

(P=0004)

1

C0

5

F0

5

2

C2

no

dif

fere

nce

inre

du

ctio

n

and

con

tro

lo

f

colo

niz

atio

n

ND

Ak

iyam

a

etal

94

R

NB

SC

FL

C2

00

mg

day

po

ver

sus

AM

B8

00

mg

middot3d

ayp

o

D0

chem

oth

erap

y

un

til

PM

Ngt

50

0m

m3

71

59

ND

ND

1

3

2

9

ND

Ph

ilp

ott

-Ho

war

d

etal

91

R

NB

MC

FL

C5

0m

gd

ayp

ov

ersu

s

AM

B2

gd

ayp

oo

r

ny

stat

in4middot

10

6U

day

bef

ore

chem

oth

erap

y

un

til

PM

Ngt

10

3m

m3

or

4w

eek

s

26

9

26

7

4

12

(P=0001)

2

9

(Plt0001)

2

C1

F1

4

C3

5

F

05

sim

ilar

ND

Meu

nie

ret

al

95

R

NB

SC

FL

Cp

o2

00

mg

day

ver

sus

AM

Bp

o4

30

mg

day

D-2

neu

tro

pen

ia

un

til

PM

Ngt

10

3m

m3

30

(9B

MT

)

29

(9B

MT

)

7

13

0

3

14

C

7

F

7

17

C

10

F7

ND

17

21

Roze

nber

g-A

rska

etal

96

R

NB

SC

FL

C5

0m

gd

ayp

ov

ersu

s

AM

B4

00

mgmiddot4

day

po

D0

neu

tro

pen

ia

un

til

PM

Ngt

50

0m

m3

25

25

ND

0 4

4

C0

F4

4

C4

F0

52

16

ND

Bra

mm

eret

al

97

C

NB

F

LC

50

mg

day

NR

12

62

7

MC

po

ver

sus

ora

l

po

lyen

es

12

24

5

(su

spec

ted

fun

gal

infe

ctio

ns)

ND

ND

ND

ND

Rr

and

om

ized

DB

do

uble

bli

nd

NB

no

tbli

nd

SB

sin

gle

bli

nd

SC

sin

gle

cen

tre

MC

mult

icen

tre

FL

Cf

luco

naz

ole

po

ora

liv

in

trav

eno

us

EO

Te

nd

oftr

eatm

ent

ND

no

tdo

ne

CC

andida

sp

Ff

ilam

ento

us

fun

gi

PM

N

po

lym

orp

ho

nu

clea

rce

lls

BM

T

bo

ne

mar

row

tran

spla

nta

tio

n

D

day

q

id

fou

rti

mes

ad

ay

Val

ues

giv

enin

bo

ldfa

cear

est

atis

tica

lly

sign

ific

ant

Review

394

grade recommendation (A-I) among allogeneic bone marrowrecipients but not in the setting of autologous BMT or acuteleukaemia (httpwwwsrlforgDataDocumentsHTMLO2_refenticls_OA-recommendations20040513asp date last accessed26 December 2005) Thus in the light of the previously describedmeta-analysis fluconazole might be appropriate in neutropenicpatients with a high risk of fungal infection ie those with longduration of neutropenia prolonged corticosteroid therapy butprobably other drugs will be better choices

Fluconazole as prophylaxis for systemic

candidiasis in ICU adults

The extent of the problem There is an increasing incidence of bothbacterial and fungal sepsis occurring in ICU patients A USstudy found that the absolute number of deaths due to invasivemycoses rose from 1557 in 1980 to 6534 in 1997104 Althoughmuch of this increase was associated with fungal infections relatedto HIV there were also marked increases in deaths due to can-didiasis aspergillosis and other mycoses in the non-HIV popula-tion A UK study looking at the outcome of candidaemia infectionsreported 187 episodes of candidaemia per 100 000 finished con-sultant episodes Of them 454 occurred in an ICU setting andC albicans was isolated in 65 of cases105 A Swiss study foundthat two-thirds of episodes of candidaemia occurred in ICU or onsurgical wards with invasive candidiasis occurring 5ndash10 timesmore frequently in an ICU setting than on other wards106

Strikingly in spite of all therapeutic innovations in the field ofantifungal therapy the crude and attributable mortality of nosoco-mial fungaemias have not decreased over the past 15 years(38)107

How are patients at risk of invasive candidiasis identified Thediagnosis of invasive candidiasis may be difficult due to the highfrequency of colonization especially in patients who are on broadspectrum antibiotics A prospective study of non-neutropenicpatients in whom Candida species were isolated found that diges-tive and respiratory samples and the isolation of non-albicansspecies were risk factors for invasive candidiasis108 Additionallythe most significant risk factors for invasive candidaemia identifiedin a surgical ICU in those who had undergone surgery were priorsurgery acute renal failure receipt of total parenteral nutrition andthe presence of a central venous catheter109 This study also foundthat administration of an antifungal agent was associated withdecreased risk for invasive candidal infection For critically illsurgical patients Pittet et al110 proposed a Candida colonizationindex based on the ratio between the number of colonized sites andthe number of sites tested Although its use in hospital practice iscomplex expensive and time-consuming this index was highlypredictive of invasive candidiasis indeed a threshold of 05 ormore correctly identified the infected patients an average of 6days before the documented candidiasis An alternative approachhas been considered using both anti-Candida antibody and antigentitres111 A high concordance between the two has been observedfor patients with invasive candidal disease compared with patientswho were only colonized with Candida Sensitivity and specificityreached 100 and 833 respectively when the two tests werecombined112

Studies that have been done A recent paper has highlighted theimportance of appropriate trial design of antifungal prophylaxisand the need for appropriate assessment of risk factors to identify

those patients who are at higher risk113 Fluconazole has previouslybeen assessed as a prophylactic agent in ITU settings with contra-dictory results

Concerns over a shift inCandida isolates that are less susceptibleor resistant to fluconazole may be balanced against the justificationof using it in appropriately identified high-risk patients114

For Three prospective randomized placebo-controlled trials haveemphasized the efficacy of fluconazole in that setting (see Table 9)In one study 260 critically ill surgical patients staying in ICU forgt3 days mainly pre-hepatic transplantation patients were ran-domly assigned to either placebo or 400 mg of fluconazole perday The risk of fungal infection was reduced by 55 in the flu-conazole group compared with the control group who experienced15 of invasive infections115 In a small study of 43 surgicalpatients with recurrent gastrointestinal leaks or perforations theuse of fluconazole prophylaxis resulted in decreased isolation ofCandida in surveillance cultures and in a decrease in candidalperitonitis 4 versus 35 with a decrease in global invasivecandidiasis (9 versus 35)116 A slightly different approachwas used in a study of 204 critically ill patients in surgical andmedical ICU where fluconazole was used as part of a selectivedigestive decontamination regimen28 These patients appear tomore closely represent a typical group of ICU patients InvasiveCandida infections occurred less frequently in 8 of the flucona-zole group compared with 20 of the placebo group and no shifttowards non-albicans species was observed

Several reviews of historical cohorts have provided similarresults A recent retrospective review in a surgical ICU comparingthe use of fluconazole prophylaxis versus a historical cohort foundthat prophylaxis decreased the incidence of candidaemia and didnot find an increase in non-albicans species117 No reduction ofmortality with fluconazole was observed Secondary Candidainfections in high-risk patients with trauma occurred in 962(145) patients who did not receive fluconazole prophylaxiscompared with 3145 (2) of a historical cohort who did118

In another randomized prospective study of bacterial septicshock fluconazole had a measurable positive impact on survivalalthough no fungal infection was diagnosed This unclear benefi-cial effect might be related to fluconazolersquos observed ability toenhance the bactericidal activity of neutrophils or to prevent Can-dida spp infection which was not diagnosed by standard bloodcultures which are known to be relatively insensitive119120

Against One group of patients at increased risk of invasivecandidiasis includes those who have undergone recent liver trans-plantation In a previously cited prospective study of 35 post-liver-transplantation patients patients with C albicans infectionswere less likely to have received antifungal prophylaxis thanthose with non-albicans Candida infections (136 versus 50P = 004) Non-albicans Candida infections and prior antifungalprophylaxis correlated with poorer outcome49 A further studylooked at 125 critically ill patients who received either fluconazoleprophylaxis or placebo during their entire stay in ICU121 Therewere no significant differences in the incidence of candidal infec-tions nor any difference in the mortality or length of stay on ICU Inthe study performed by Pelz et al115 among pre-liver-transplanta-tion patients no benefit of fluconazole on survival could be noticedalthough a clear reduction of fungal infection was observed

There are however concerns that the use of prophylacticfluconazole in critical care patients favours the emergence of

Review

395

Table

7

Stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

pla

ceb

oo

rn

otr

eatm

ent

inn

eutr

op

enic

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

n

atth

eE

OT

Dea

th

Lav

erd

iere

etal

81

R

DB

PC

M

C

FL

C4

00

mg

day

po

ver

sus

pla

ceb

o

wit

hin

72

h

po

st-i

nit

iati

on

of

chem

oth

erap

y

un

til

PM

N

gt5

00

mm

3

13

5(6

0B

MT

)

13

1(5

8B

MT

)

ND

ND

3

17

Plt0001

31

75

ND

Ro

tste

inet

al

84

R

DB

F

LC

40

0m

gd

ayw

ith

in7

2h

14

1(6

2B

MT

)N

D7

3

015ndash023

ND

PC

M

Cp

ov

ersu

sp

lace

bo

po

st-i

nit

iati

on

of

chem

oth

erap

yu

nti

l

PM

Ngt

50

0m

m3

13

3(5

8B

MT

)18

(P=002)

16

(P=00001)

039ndash030

fungalindex

colonization

(Plt00001)

Ker

net

al

86

R

DB

SC

FL

C4

00

mg

day

po

ver

sus

no

trea

tmen

t

36

32

ND

ND

6

6

ND

no

dif

fere

nce

Sch

affn

eret

al

87

R

DB

PC

S

C

FL

C4

00

mg

day

po

iv

ver

sus

pla

ceb

o

adm

issi

on

un

til

sust

ain

edP

MN

gt5

00

mm

3

75

76

ND

1

12

(P

=0

01

8)

8

C0

F8

9

C5

F4

8

36

(Plt00001)

6

7

Yam

acet

al

85

R

NB

SC

FL

C4

00

mg

day

po

ver

sus

no

D0

chem

oth

erap

y

un

til

PM

N

41

29

ND

ND

9

31

(Plt005)

ND

ND

trea

tmen

tgt

2middot

10

3m

m3

Ch

and

rase

kar

83

R

DB

PC

S

C

FL

C4

00

mg

day

po

ver

sus

pla

ceb

o

D0

chem

oth

erap

yo

r

con

dit

ion

ing

or

reg

imen

un

til

D+

7af

ter

PM

Ngt

10

3m

l

23

(11

BM

T)

24

(11

BM

T)

ND

34

79

(P=

00

00

2)

10

C

0

F

10

5

C5

F0

ND

17

13

Win

sto

n8

2R

D

B

PC

M

C

FL

Cp

o4

00

mg

day

po

iv

ver

sus

pla

ceb

o

D0

chem

oth

erap

y

un

til

PM

Ngt

10

3m

l

12

4

13

2

9

21

(P=

00

2)

6

15

(Plt

00

1)

4

C1

F3

8

C4

5

F

35

29

68

(P=

00

01

)

21

18

R

rand

om

ized

D

B

do

uble

bli

nd

N

B

no

tb

lin

d

PC

p

lace

bo

con

troll

ed

SC

si

ng

lece

ntr

eM

C

mult

icen

tre

FL

C

flu

conaz

ole

p

o

ora

liv

in

trav

eno

us

EO

T

end

of

trea

tmen

tN

D

no

td

on

eC

Candida

sp

F

fila

men

tou

sfu

ng

iP

MN

p

oly

mo

rph

on

ucl

ear

cell

sB

MT

b

on

em

arro

wtr

ansp

lan

tati

on

D

d

ay

Val

ues

giv

enin

bo

ldfa

cear

est

atis

tica

lly

sign

ific

ant

Review

393

Table

8

Co

mp

arat

ive

stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

oth

eran

tifu

ng

als

inn

eutr

op

enic

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

nat

the

EO

TD

eath

Morg

enst

ern

etal

89

R

SB

MC

FL

C1

00

mg

day

po

ver

sus

itra

con

azo

le

25

mg

kg

twic

e

ad

ayp

o

beg

inn

ing

con

dit

ion

ing

reg

imen

un

til

PM

N

gt1

03m

m3gt

1w

eek

22

7

(12

0B

MT

)

21

8

(11

0B

MT

)

ND

5

2

3

C1

F2

1

C1

ND

4

1

Eg

ger

etal

88

R

NB

SC

FL

C4

00

mg

day

ivp

ov

ersu

sn

yst

atin

24middot

10

6U

middot3d

ayp

o

fro

mh

osp

ital

izat

ion

in

iso

lati

on

un

itu

nti

l

end

of

neu

tro

pen

ia

43

(14

BM

T)

46

(19

BM

T)

2

4

0

0

2

4

ND

ND

Bo

dey

etal

98

R

NB

SC

FL

C4

00

mg

day

po

ver

sus

AM

B

05

mg

kgmiddot3

wee

kiv

fro

mD

0ch

emo

ther

apy

un

til

PM

Ngt

10

3m

m3

41

36

4

8

0

0

4

8

18

15

15

9

Ell

iset

al

90

R

DB

SC

FL

Cp

o2

00

mg

day

ver

sus

clo

trim

azo

le

(10

mg

qid

)+

my

cost

atin

50

00

00

IUq

id

adm

issi

on

un

til

PM

Ngt

10

3m

m3

42

(10

BM

T)

48

(13

BM

T)

95

35

(Plt

00

1)

2

13

5

21

ND

19

35

(Plt004)

Men

ich

etti

R

NB

F

LC

15

0m

gd

ayp

oD

-3to

D-1

bef

ore

42

03

5

2

15

N

D1

0

etal

93

MC

ver

sus

AM

B5

00

mg

middot4d

ayp

o

chem

oth

erap

yu

nti

l

PM

Ngt

10

3m

m3

40

05

3

2

1

0

Nin

aneet

al

92

R

NB

MC

chil

dre

n

FL

Cp

o3

mg

kg

day

ver

sus

ny

stat

inp

o

50

00

0U

kg

qid

or

AM

B

25

mg

kg

qid

po

48

hw

ith

inin

itia

tio

n

of

chem

oth

erap

y

un

til

PM

Ngt

10

3m

m3

24

5

25

7

2

8

(P=0002)

1

6

(P=0004)

1

C0

5

F0

5

2

C2

no

dif

fere

nce

inre

du

ctio

n

and

con

tro

lo

f

colo

niz

atio

n

ND

Ak

iyam

a

etal

94

R

NB

SC

FL

C2

00

mg

day

po

ver

sus

AM

B8

00

mg

middot3d

ayp

o

D0

chem

oth

erap

y

un

til

PM

Ngt

50

0m

m3

71

59

ND

ND

1

3

2

9

ND

Ph

ilp

ott

-Ho

war

d

etal

91

R

NB

MC

FL

C5

0m

gd

ayp

ov

ersu

s

AM

B2

gd

ayp

oo

r

ny

stat

in4middot

10

6U

day

bef

ore

chem

oth

erap

y

un

til

PM

Ngt

10

3m

m3

or

4w

eek

s

26

9

26

7

4

12

(P=0001)

2

9

(Plt0001)

2

C1

F1

4

C3

5

F

05

sim

ilar

ND

Meu

nie

ret

al

95

R

NB

SC

FL

Cp

o2

00

mg

day

ver

sus

AM

Bp

o4

30

mg

day

D-2

neu

tro

pen

ia

un

til

PM

Ngt

10

3m

m3

30

(9B

MT

)

29

(9B

MT

)

7

13

0

3

14

C

7

F

7

17

C

10

F7

ND

17

21

Roze

nber

g-A

rska

etal

96

R

NB

SC

FL

C5

0m

gd

ayp

ov

ersu

s

AM

B4

00

mgmiddot4

day

po

D0

neu

tro

pen

ia

un

til

PM

Ngt

50

0m

m3

25

25

ND

0 4

4

C0

F4

4

C4

F0

52

16

ND

Bra

mm

eret

al

97

C

NB

F

LC

50

mg

day

NR

12

62

7

MC

po

ver

sus

ora

l

po

lyen

es

12

24

5

(su

spec

ted

fun

gal

infe

ctio

ns)

ND

ND

ND

ND

Rr

and

om

ized

DB

do

uble

bli

nd

NB

no

tbli

nd

SB

sin

gle

bli

nd

SC

sin

gle

cen

tre

MC

mult

icen

tre

FL

Cf

luco

naz

ole

po

ora

liv

in

trav

eno

us

EO

Te

nd

oftr

eatm

ent

ND

no

tdo

ne

CC

andida

sp

Ff

ilam

ento

us

fun

gi

PM

N

po

lym

orp

ho

nu

clea

rce

lls

BM

T

bo

ne

mar

row

tran

spla

nta

tio

n

D

day

q

id

fou

rti

mes

ad

ay

Val

ues

giv

enin

bo

ldfa

cear

est

atis

tica

lly

sign

ific

ant

Review

394

grade recommendation (A-I) among allogeneic bone marrowrecipients but not in the setting of autologous BMT or acuteleukaemia (httpwwwsrlforgDataDocumentsHTMLO2_refenticls_OA-recommendations20040513asp date last accessed26 December 2005) Thus in the light of the previously describedmeta-analysis fluconazole might be appropriate in neutropenicpatients with a high risk of fungal infection ie those with longduration of neutropenia prolonged corticosteroid therapy butprobably other drugs will be better choices

Fluconazole as prophylaxis for systemic

candidiasis in ICU adults

The extent of the problem There is an increasing incidence of bothbacterial and fungal sepsis occurring in ICU patients A USstudy found that the absolute number of deaths due to invasivemycoses rose from 1557 in 1980 to 6534 in 1997104 Althoughmuch of this increase was associated with fungal infections relatedto HIV there were also marked increases in deaths due to can-didiasis aspergillosis and other mycoses in the non-HIV popula-tion A UK study looking at the outcome of candidaemia infectionsreported 187 episodes of candidaemia per 100 000 finished con-sultant episodes Of them 454 occurred in an ICU setting andC albicans was isolated in 65 of cases105 A Swiss study foundthat two-thirds of episodes of candidaemia occurred in ICU or onsurgical wards with invasive candidiasis occurring 5ndash10 timesmore frequently in an ICU setting than on other wards106

Strikingly in spite of all therapeutic innovations in the field ofantifungal therapy the crude and attributable mortality of nosoco-mial fungaemias have not decreased over the past 15 years(38)107

How are patients at risk of invasive candidiasis identified Thediagnosis of invasive candidiasis may be difficult due to the highfrequency of colonization especially in patients who are on broadspectrum antibiotics A prospective study of non-neutropenicpatients in whom Candida species were isolated found that diges-tive and respiratory samples and the isolation of non-albicansspecies were risk factors for invasive candidiasis108 Additionallythe most significant risk factors for invasive candidaemia identifiedin a surgical ICU in those who had undergone surgery were priorsurgery acute renal failure receipt of total parenteral nutrition andthe presence of a central venous catheter109 This study also foundthat administration of an antifungal agent was associated withdecreased risk for invasive candidal infection For critically illsurgical patients Pittet et al110 proposed a Candida colonizationindex based on the ratio between the number of colonized sites andthe number of sites tested Although its use in hospital practice iscomplex expensive and time-consuming this index was highlypredictive of invasive candidiasis indeed a threshold of 05 ormore correctly identified the infected patients an average of 6days before the documented candidiasis An alternative approachhas been considered using both anti-Candida antibody and antigentitres111 A high concordance between the two has been observedfor patients with invasive candidal disease compared with patientswho were only colonized with Candida Sensitivity and specificityreached 100 and 833 respectively when the two tests werecombined112

Studies that have been done A recent paper has highlighted theimportance of appropriate trial design of antifungal prophylaxisand the need for appropriate assessment of risk factors to identify

those patients who are at higher risk113 Fluconazole has previouslybeen assessed as a prophylactic agent in ITU settings with contra-dictory results

Concerns over a shift inCandida isolates that are less susceptibleor resistant to fluconazole may be balanced against the justificationof using it in appropriately identified high-risk patients114

For Three prospective randomized placebo-controlled trials haveemphasized the efficacy of fluconazole in that setting (see Table 9)In one study 260 critically ill surgical patients staying in ICU forgt3 days mainly pre-hepatic transplantation patients were ran-domly assigned to either placebo or 400 mg of fluconazole perday The risk of fungal infection was reduced by 55 in the flu-conazole group compared with the control group who experienced15 of invasive infections115 In a small study of 43 surgicalpatients with recurrent gastrointestinal leaks or perforations theuse of fluconazole prophylaxis resulted in decreased isolation ofCandida in surveillance cultures and in a decrease in candidalperitonitis 4 versus 35 with a decrease in global invasivecandidiasis (9 versus 35)116 A slightly different approachwas used in a study of 204 critically ill patients in surgical andmedical ICU where fluconazole was used as part of a selectivedigestive decontamination regimen28 These patients appear tomore closely represent a typical group of ICU patients InvasiveCandida infections occurred less frequently in 8 of the flucona-zole group compared with 20 of the placebo group and no shifttowards non-albicans species was observed

Several reviews of historical cohorts have provided similarresults A recent retrospective review in a surgical ICU comparingthe use of fluconazole prophylaxis versus a historical cohort foundthat prophylaxis decreased the incidence of candidaemia and didnot find an increase in non-albicans species117 No reduction ofmortality with fluconazole was observed Secondary Candidainfections in high-risk patients with trauma occurred in 962(145) patients who did not receive fluconazole prophylaxiscompared with 3145 (2) of a historical cohort who did118

In another randomized prospective study of bacterial septicshock fluconazole had a measurable positive impact on survivalalthough no fungal infection was diagnosed This unclear benefi-cial effect might be related to fluconazolersquos observed ability toenhance the bactericidal activity of neutrophils or to prevent Can-dida spp infection which was not diagnosed by standard bloodcultures which are known to be relatively insensitive119120

Against One group of patients at increased risk of invasivecandidiasis includes those who have undergone recent liver trans-plantation In a previously cited prospective study of 35 post-liver-transplantation patients patients with C albicans infectionswere less likely to have received antifungal prophylaxis thanthose with non-albicans Candida infections (136 versus 50P = 004) Non-albicans Candida infections and prior antifungalprophylaxis correlated with poorer outcome49 A further studylooked at 125 critically ill patients who received either fluconazoleprophylaxis or placebo during their entire stay in ICU121 Therewere no significant differences in the incidence of candidal infec-tions nor any difference in the mortality or length of stay on ICU Inthe study performed by Pelz et al115 among pre-liver-transplanta-tion patients no benefit of fluconazole on survival could be noticedalthough a clear reduction of fungal infection was observed

There are however concerns that the use of prophylacticfluconazole in critical care patients favours the emergence of

Review

395

Table

8

Co

mp

arat

ive

stu

die

so

np

rop

hy

lact

icfl

uco

naz

ole

ver

sus

oth

eran

tifu

ng

als

inn

eutr

op

enic

pat

ien

ts

Ref

eren

ce

Stu

dy

des

ign

Reg

imen

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

ts

Pro

ven

Candida

sp

infe

ctio

ns

Su

per

fici

al

infe

ctio

ns

Inv

asiv

e

infe

ctio

ns

Candida

sp

colo

niz

atio

nat

the

EO

TD

eath

Morg

enst

ern

etal

89

R

SB

MC

FL

C1

00

mg

day

po

ver

sus

itra

con

azo

le

25

mg

kg

twic

e

ad

ayp

o

beg

inn

ing

con

dit

ion

ing

reg

imen

un

til

PM

N

gt1

03m

m3gt

1w

eek

22

7

(12

0B

MT

)

21

8

(11

0B

MT

)

ND

5

2

3

C1

F2

1

C1

ND

4

1

Eg

ger

etal

88

R

NB

SC

FL

C4

00

mg

day

ivp

ov

ersu

sn

yst

atin

24middot

10

6U

middot3d

ayp

o

fro

mh

osp

ital

izat

ion

in

iso

lati

on

un

itu

nti

l

end

of

neu

tro

pen

ia

43

(14

BM

T)

46

(19

BM

T)

2

4

0

0

2

4

ND

ND

Bo

dey

etal

98

R

NB

SC

FL

C4

00

mg

day

po

ver

sus

AM

B

05

mg

kgmiddot3

wee

kiv

fro

mD

0ch

emo

ther

apy

un

til

PM

Ngt

10

3m

m3

41

36

4

8

0

0

4

8

18

15

15

9

Ell

iset

al

90

R

DB

SC

FL

Cp

o2

00

mg

day

ver

sus

clo

trim

azo

le

(10

mg

qid

)+

my

cost

atin

50

00

00

IUq

id

adm

issi

on

un

til

PM

Ngt

10

3m

m3

42

(10

BM

T)

48

(13

BM

T)

95

35

(Plt

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(Plt004)

Men

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92

R

NB

MC

chil

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n

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Cp

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mg

kg

day

ver

sus

ny

stat

inp

o

50

00

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kg

qid

or

AM

B

25

mg

kg

qid

po

48

hw

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inin

itia

tio

n

of

chem

oth

erap

y

un

til

PM

Ngt

10

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24

5

25

7

2

8

(P=0002)

1

6

(P=0004)

1

C0

5

F0

5

2

C2

no

dif

fere

nce

inre

du

ctio

n

and

con

tro

lo

f

colo

niz

atio

n

ND

Ak

iyam

a

etal

94

R

NB

SC

FL

C2

00

mg

day

po

ver

sus

AM

B8

00

mg

middot3d

ayp

o

D0

chem

oth

erap

y

un

til

PM

Ngt

50

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m3

71

59

ND

ND

1

3

2

9

ND

Ph

ilp

ott

-Ho

war

d

etal

91

R

NB

MC

FL

C5

0m

gd

ayp

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s

AM

B2

gd

ayp

oo

r

ny

stat

in4middot

10

6U

day

bef

ore

chem

oth

erap

y

un

til

PM

Ngt

10

3m

m3

or

4w

eek

s

26

9

26

7

4

12

(P=0001)

2

9

(Plt0001)

2

C1

F1

4

C3

5

F

05

sim

ilar

ND

Meu

nie

ret

al

95

R

NB

SC

FL

Cp

o2

00

mg

day

ver

sus

AM

Bp

o4

30

mg

day

D-2

neu

tro

pen

ia

un

til

PM

Ngt

10

3m

m3

30

(9B

MT

)

29

(9B

MT

)

7

13

0

3

14

C

7

F

7

17

C

10

F7

ND

17

21

Roze

nber

g-A

rska

etal

96

R

NB

SC

FL

C5

0m

gd

ayp

ov

ersu

s

AM

B4

00

mgmiddot4

day

po

D0

neu

tro

pen

ia

un

til

PM

Ngt

50

0m

m3

25

25

ND

0 4

4

C0

F4

4

C4

F0

52

16

ND

Bra

mm

eret

al

97

C

NB

F

LC

50

mg

day

NR

12

62

7

MC

po

ver

sus

ora

l

po

lyen

es

12

24

5

(su

spec

ted

fun

gal

infe

ctio

ns)

ND

ND

ND

ND

Rr

and

om

ized

DB

do

uble

bli

nd

NB

no

tbli

nd

SB

sin

gle

bli

nd

SC

sin

gle

cen

tre

MC

mult

icen

tre

FL

Cf

luco

naz

ole

po

ora

liv

in

trav

eno

us

EO

Te

nd

oftr

eatm

ent

ND

no

tdo

ne

CC

andida

sp

Ff

ilam

ento

us

fun

gi

PM

N

po

lym

orp

ho

nu

clea

rce

lls

BM

T

bo

ne

mar

row

tran

spla

nta

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n

D

day

q

id

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mes

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ay

Val

ues

giv

enin

bo

ldfa

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est

atis

tica

lly

sign

ific

ant

Review

394

grade recommendation (A-I) among allogeneic bone marrowrecipients but not in the setting of autologous BMT or acuteleukaemia (httpwwwsrlforgDataDocumentsHTMLO2_refenticls_OA-recommendations20040513asp date last accessed26 December 2005) Thus in the light of the previously describedmeta-analysis fluconazole might be appropriate in neutropenicpatients with a high risk of fungal infection ie those with longduration of neutropenia prolonged corticosteroid therapy butprobably other drugs will be better choices

Fluconazole as prophylaxis for systemic

candidiasis in ICU adults

The extent of the problem There is an increasing incidence of bothbacterial and fungal sepsis occurring in ICU patients A USstudy found that the absolute number of deaths due to invasivemycoses rose from 1557 in 1980 to 6534 in 1997104 Althoughmuch of this increase was associated with fungal infections relatedto HIV there were also marked increases in deaths due to can-didiasis aspergillosis and other mycoses in the non-HIV popula-tion A UK study looking at the outcome of candidaemia infectionsreported 187 episodes of candidaemia per 100 000 finished con-sultant episodes Of them 454 occurred in an ICU setting andC albicans was isolated in 65 of cases105 A Swiss study foundthat two-thirds of episodes of candidaemia occurred in ICU or onsurgical wards with invasive candidiasis occurring 5ndash10 timesmore frequently in an ICU setting than on other wards106

Strikingly in spite of all therapeutic innovations in the field ofantifungal therapy the crude and attributable mortality of nosoco-mial fungaemias have not decreased over the past 15 years(38)107

How are patients at risk of invasive candidiasis identified Thediagnosis of invasive candidiasis may be difficult due to the highfrequency of colonization especially in patients who are on broadspectrum antibiotics A prospective study of non-neutropenicpatients in whom Candida species were isolated found that diges-tive and respiratory samples and the isolation of non-albicansspecies were risk factors for invasive candidiasis108 Additionallythe most significant risk factors for invasive candidaemia identifiedin a surgical ICU in those who had undergone surgery were priorsurgery acute renal failure receipt of total parenteral nutrition andthe presence of a central venous catheter109 This study also foundthat administration of an antifungal agent was associated withdecreased risk for invasive candidal infection For critically illsurgical patients Pittet et al110 proposed a Candida colonizationindex based on the ratio between the number of colonized sites andthe number of sites tested Although its use in hospital practice iscomplex expensive and time-consuming this index was highlypredictive of invasive candidiasis indeed a threshold of 05 ormore correctly identified the infected patients an average of 6days before the documented candidiasis An alternative approachhas been considered using both anti-Candida antibody and antigentitres111 A high concordance between the two has been observedfor patients with invasive candidal disease compared with patientswho were only colonized with Candida Sensitivity and specificityreached 100 and 833 respectively when the two tests werecombined112

Studies that have been done A recent paper has highlighted theimportance of appropriate trial design of antifungal prophylaxisand the need for appropriate assessment of risk factors to identify

those patients who are at higher risk113 Fluconazole has previouslybeen assessed as a prophylactic agent in ITU settings with contra-dictory results

Concerns over a shift inCandida isolates that are less susceptibleor resistant to fluconazole may be balanced against the justificationof using it in appropriately identified high-risk patients114

For Three prospective randomized placebo-controlled trials haveemphasized the efficacy of fluconazole in that setting (see Table 9)In one study 260 critically ill surgical patients staying in ICU forgt3 days mainly pre-hepatic transplantation patients were ran-domly assigned to either placebo or 400 mg of fluconazole perday The risk of fungal infection was reduced by 55 in the flu-conazole group compared with the control group who experienced15 of invasive infections115 In a small study of 43 surgicalpatients with recurrent gastrointestinal leaks or perforations theuse of fluconazole prophylaxis resulted in decreased isolation ofCandida in surveillance cultures and in a decrease in candidalperitonitis 4 versus 35 with a decrease in global invasivecandidiasis (9 versus 35)116 A slightly different approachwas used in a study of 204 critically ill patients in surgical andmedical ICU where fluconazole was used as part of a selectivedigestive decontamination regimen28 These patients appear tomore closely represent a typical group of ICU patients InvasiveCandida infections occurred less frequently in 8 of the flucona-zole group compared with 20 of the placebo group and no shifttowards non-albicans species was observed

Several reviews of historical cohorts have provided similarresults A recent retrospective review in a surgical ICU comparingthe use of fluconazole prophylaxis versus a historical cohort foundthat prophylaxis decreased the incidence of candidaemia and didnot find an increase in non-albicans species117 No reduction ofmortality with fluconazole was observed Secondary Candidainfections in high-risk patients with trauma occurred in 962(145) patients who did not receive fluconazole prophylaxiscompared with 3145 (2) of a historical cohort who did118

In another randomized prospective study of bacterial septicshock fluconazole had a measurable positive impact on survivalalthough no fungal infection was diagnosed This unclear benefi-cial effect might be related to fluconazolersquos observed ability toenhance the bactericidal activity of neutrophils or to prevent Can-dida spp infection which was not diagnosed by standard bloodcultures which are known to be relatively insensitive119120

Against One group of patients at increased risk of invasivecandidiasis includes those who have undergone recent liver trans-plantation In a previously cited prospective study of 35 post-liver-transplantation patients patients with C albicans infectionswere less likely to have received antifungal prophylaxis thanthose with non-albicans Candida infections (136 versus 50P = 004) Non-albicans Candida infections and prior antifungalprophylaxis correlated with poorer outcome49 A further studylooked at 125 critically ill patients who received either fluconazoleprophylaxis or placebo during their entire stay in ICU121 Therewere no significant differences in the incidence of candidal infec-tions nor any difference in the mortality or length of stay on ICU Inthe study performed by Pelz et al115 among pre-liver-transplanta-tion patients no benefit of fluconazole on survival could be noticedalthough a clear reduction of fungal infection was observed

There are however concerns that the use of prophylacticfluconazole in critical care patients favours the emergence of

Review

395

grade recommendation (A-I) among allogeneic bone marrowrecipients but not in the setting of autologous BMT or acuteleukaemia (httpwwwsrlforgDataDocumentsHTMLO2_refenticls_OA-recommendations20040513asp date last accessed26 December 2005) Thus in the light of the previously describedmeta-analysis fluconazole might be appropriate in neutropenicpatients with a high risk of fungal infection ie those with longduration of neutropenia prolonged corticosteroid therapy butprobably other drugs will be better choices

Fluconazole as prophylaxis for systemic

candidiasis in ICU adults

The extent of the problem There is an increasing incidence of bothbacterial and fungal sepsis occurring in ICU patients A USstudy found that the absolute number of deaths due to invasivemycoses rose from 1557 in 1980 to 6534 in 1997104 Althoughmuch of this increase was associated with fungal infections relatedto HIV there were also marked increases in deaths due to can-didiasis aspergillosis and other mycoses in the non-HIV popula-tion A UK study looking at the outcome of candidaemia infectionsreported 187 episodes of candidaemia per 100 000 finished con-sultant episodes Of them 454 occurred in an ICU setting andC albicans was isolated in 65 of cases105 A Swiss study foundthat two-thirds of episodes of candidaemia occurred in ICU or onsurgical wards with invasive candidiasis occurring 5ndash10 timesmore frequently in an ICU setting than on other wards106

Strikingly in spite of all therapeutic innovations in the field ofantifungal therapy the crude and attributable mortality of nosoco-mial fungaemias have not decreased over the past 15 years(38)107

How are patients at risk of invasive candidiasis identified Thediagnosis of invasive candidiasis may be difficult due to the highfrequency of colonization especially in patients who are on broadspectrum antibiotics A prospective study of non-neutropenicpatients in whom Candida species were isolated found that diges-tive and respiratory samples and the isolation of non-albicansspecies were risk factors for invasive candidiasis108 Additionallythe most significant risk factors for invasive candidaemia identifiedin a surgical ICU in those who had undergone surgery were priorsurgery acute renal failure receipt of total parenteral nutrition andthe presence of a central venous catheter109 This study also foundthat administration of an antifungal agent was associated withdecreased risk for invasive candidal infection For critically illsurgical patients Pittet et al110 proposed a Candida colonizationindex based on the ratio between the number of colonized sites andthe number of sites tested Although its use in hospital practice iscomplex expensive and time-consuming this index was highlypredictive of invasive candidiasis indeed a threshold of 05 ormore correctly identified the infected patients an average of 6days before the documented candidiasis An alternative approachhas been considered using both anti-Candida antibody and antigentitres111 A high concordance between the two has been observedfor patients with invasive candidal disease compared with patientswho were only colonized with Candida Sensitivity and specificityreached 100 and 833 respectively when the two tests werecombined112

Studies that have been done A recent paper has highlighted theimportance of appropriate trial design of antifungal prophylaxisand the need for appropriate assessment of risk factors to identify

those patients who are at higher risk113 Fluconazole has previouslybeen assessed as a prophylactic agent in ITU settings with contra-dictory results

Concerns over a shift inCandida isolates that are less susceptibleor resistant to fluconazole may be balanced against the justificationof using it in appropriately identified high-risk patients114

For Three prospective randomized placebo-controlled trials haveemphasized the efficacy of fluconazole in that setting (see Table 9)In one study 260 critically ill surgical patients staying in ICU forgt3 days mainly pre-hepatic transplantation patients were ran-domly assigned to either placebo or 400 mg of fluconazole perday The risk of fungal infection was reduced by 55 in the flu-conazole group compared with the control group who experienced15 of invasive infections115 In a small study of 43 surgicalpatients with recurrent gastrointestinal leaks or perforations theuse of fluconazole prophylaxis resulted in decreased isolation ofCandida in surveillance cultures and in a decrease in candidalperitonitis 4 versus 35 with a decrease in global invasivecandidiasis (9 versus 35)116 A slightly different approachwas used in a study of 204 critically ill patients in surgical andmedical ICU where fluconazole was used as part of a selectivedigestive decontamination regimen28 These patients appear tomore closely represent a typical group of ICU patients InvasiveCandida infections occurred less frequently in 8 of the flucona-zole group compared with 20 of the placebo group and no shifttowards non-albicans species was observed

Several reviews of historical cohorts have provided similarresults A recent retrospective review in a surgical ICU comparingthe use of fluconazole prophylaxis versus a historical cohort foundthat prophylaxis decreased the incidence of candidaemia and didnot find an increase in non-albicans species117 No reduction ofmortality with fluconazole was observed Secondary Candidainfections in high-risk patients with trauma occurred in 962(145) patients who did not receive fluconazole prophylaxiscompared with 3145 (2) of a historical cohort who did118

In another randomized prospective study of bacterial septicshock fluconazole had a measurable positive impact on survivalalthough no fungal infection was diagnosed This unclear benefi-cial effect might be related to fluconazolersquos observed ability toenhance the bactericidal activity of neutrophils or to prevent Can-dida spp infection which was not diagnosed by standard bloodcultures which are known to be relatively insensitive119120

Against One group of patients at increased risk of invasivecandidiasis includes those who have undergone recent liver trans-plantation In a previously cited prospective study of 35 post-liver-transplantation patients patients with C albicans infectionswere less likely to have received antifungal prophylaxis thanthose with non-albicans Candida infections (136 versus 50P = 004) Non-albicans Candida infections and prior antifungalprophylaxis correlated with poorer outcome49 A further studylooked at 125 critically ill patients who received either fluconazoleprophylaxis or placebo during their entire stay in ICU121 Therewere no significant differences in the incidence of candidal infec-tions nor any difference in the mortality or length of stay on ICU Inthe study performed by Pelz et al115 among pre-liver-transplanta-tion patients no benefit of fluconazole on survival could be noticedalthough a clear reduction of fungal infection was observed

There are however concerns that the use of prophylacticfluconazole in critical care patients favours the emergence of

Review

395

non-albicans species some of which are less susceptible or resis-tant to fluconazole One review paper in 2002 suggested that therewas no evidence of therapeutic benefit with prophylactic flucona-zole used in this manner122 In a small retrospective review ofcritically ill patients on ITU who did or did not receive fluconazolethe mortality was higher in the fluconazole group and this groupalso demonstrated increased bacterial resistance There was a trendtowards increasing Candida resistance to fluconazole over theperiod of the study123

Tortorano et al124 recently reported a 20 year study on theevolving trends of candidiasis in an Italian ICU When comparingthe data from 2000 and the data from the 1980s the rate of Candidaspp invasive infections and colonization appeared stable How-ever the authors reported an increased number of mixed coloniza-tion (39 versus 6) with a reduction of colonization byC albicans (78 versus 93) and a flare up ofC glabrata involve-ment (35) Two cases of acquired resistance to fluconazole inC glabrata strains were documented MICs to other azoles werealso elevated in both cases with one case resistant to itraconazoleand less susceptible to voriconazole

In summary fluconazole prophylaxis in the ICU has been shownto reduce the incidence of invasive candidal infections in somehigh-risk patients such as those with a perforated viscus majortrauma and possible pancreatitis The role of acquired resistance tofluconazole in this setting is however unclear and prophylaxis hasnot been shown to reduce mortality Even if the epidemiology ofCandida sp infections in ITU does not display the shift towardsazole less-susceptible strains observed in the AIDS population theregular use of fluconazole prophylaxis may lead to selection ofresistant organisms Larger trials with appropriate selection ofpatients are needed This view has been reported in detail previ-ously125126

Fluconazole for prophylaxis of oesophagitis in

HIV-infected patients

Mucosal candidiasis had markedly contributed to the morbidity ofHIV-infected patients worldwide until the era of highly activeantiretroviral therapy (HAART) which led to a drastic reductionof both colonization and infection by Candida spp127 HoweverCandida is still one of the most common fungal pathogens observedin the HIV-infected population who do not have access to HAARTand candidiasis is still a concern in Europe and in United Statesamong patients with poor adherence to antiviral treatment or viro-immunological failure

Primary prophylaxis Mucosal infections are not targeted for prim-ary prophylaxis because of the effectiveness of curative antifungaltherapy in that setting the low mortality associated with mucosalcandidiasis and potential for resistant Candida spp to develop aswell as of the possibility of drug interactions

However in the pre-HAART era Powderly et al128 demon-strated in 1995 in a randomized multicentre unblinded trial thatoral fluconazole (200 mgday) compared with clotrimazoletroches was associated with fewer episodes of oesophageal andoropharyngeal candidiasis

Secondary prophylaxis When recurrences are frequent or severelong-term oral azole use may be considered to improve quality oflife Seven randomized placebo-controlled studies performed dur-ing the pre-HAART era have clearly demonstrated the efficacy ofT

able

9

Co

ntr

oll

edra

nd

om

ized

pro

spec

tiv

est

ud

ies

on

flu

con

azo

lep

rop

hy

lax

isin

ICU

s

Ref

eren

ceR

isk

fact

or

Mea

nA

PA

CH

E2

sco

reR

egim

en

Nu

mb

ero

f

pat

ien

ts

New

Candida

sp

colo

niz

atio

n

Inv

asiv

e

can

did

iasi

s

Dea

th

rate

Gar

bin

oet

al

28

mec

han

ical

ven

tila

tio

n

for

gt4

8h

wit

h

gt7

2h

exp

ecte

d

21

10

0m

giv

ver

sus

pla

ceb

o

10

3

10

1

53

78

(Plt0001)

8

20

39

41

Pel

zet

al

11

5IC

Ust

aygt

3d

ays

pre

-hep

atic

tran

spla

nta

tio

n

63

40

0m

gp

o

ver

sus

pla

ceb

o

13

0

13

0

ND

85

15

(Plt001)

14

16

Eg

gim

annet

al

11

6ab

do

min

alsu

rger

y

recu

rren

tg

astr

oin

test

inal

per

fora

tio

no

ran

asto

mo

tic

leak

ages

17

40

0m

giv

ver

sus

pla

ceb

o

23

20

15

62

(P=004)

9

35

(P=002)

30

50

ICU

in

ten

siv

eca

reu

nit

p

o

ora

liv

in

trav

eno

us

ND

n

ot

do

ne

Val

ues

giv

enin

bo

ldfa

cear

est

atis

tica

lly

sig

nif

ican

t

Review

396

fluconazole in that setting with doses ranging from 50 100 or200 mgday to 150 and 400 mgweek129ndash135 Three of themincluded more than 20 patients per arm132133135 (see Table 10)Fluconazole decreased the rate of mucosal infections caused byCandida (vaginal oropharyngeal and oesophageal) Daily regi-mens of fluconazole probably convey better protection againstnew superficial infection events Indeed Havlir et al134 observedsignificantly higher rates of thrush among weekly treated popula-tion than among daily treated (199 versus 123) with shortertime to onset of the initial episode The tolerance of fluconazolewas good Such long-term strategies raise the concern about emer-gence of fluconazole-resistant C albicans and non-albicansstrains

Pagani et al135 identified in vitro fluconazole resistance in12 patients within their cohort of 135 patients Of them eightwere receiving the fluconazole regimen and four were placebo-treated and five presented with clinical failure at the endpoint ofstudy (four receiving fluconazole and one placebo-treated) Theincidence of resistant candidiasis was not found significantly dif-ferent in these two small groups However microbiological resis-tance was significantly associated with the cumulative dose offluconazole before entry in a multiple regression analysis andpatients with clinical failure had received larger cumulativedoses of fluconazole before study entry (mean value 87 g versus29 g) In a similar approach Vazquez et al136 observed that 17of the fluconazole-treated patients had fluconazole-resistant Can-dida sp isolated in the mouth versus only 8 in the placebo groupHowever this difference was not significant

The best prophylaxis for mucosal candidiasis relies on HAARTFor patients with immuno-virological failure fluconazole appearsto be an effective prophylactic drug Noting the probable long-termemergence of resistant strains its use should be limited to thesetting of severe frequent recurrences as suggested in the recentlyupdated French guidelines for HIV care137

Fluconazole in adult neutropenic patients with

systemic candidiasis

Fluconazole is an alternative treatment to amphotericin B in neu-tropenic patients if the infecting strain is susceptible to it Thisconclusion is based on three already dated main studies of whichonly one was randomized and consisted of a small number ofaffected patients138ndash140 De Pauw et al138 showed that fluconazoleat a dose of 400 mgday cured six out of nine patients namely fourof the six patients with candidaemia one of the two patients suf-fering from generalized candidiasis and the fourth patient sufferingfrom Candida-induced meningitis The other two studies showedthat fluconazole at a dose of 400 mgday (in adults) was just aseffective and better tolerated than deoxycholate amphotericin at adose of 06ndash07 mgkgday Fluconazole in neutropenic patients isoften used successfully at higher doses such as 800 mgday (even1200 mgday) but this is not supported by published data Thecombination of fluconazole (800 mgday) and amphotericin B(07 mgkgday) has not been studied in neutropenic patientsThe IDSA is cautious not to recommend the use of fluconazoleas a first line treatment if the patientrsquos condition is not stable andorif the strain has not been identified57 In practice this limits theindication of fluconazole as initial treatment In theory at leastonly patients colonized by a strain that is usually susceptible tofluconazole (C albicans C tropicalis C parapsilosis) and whohave not received azole prophylaxis can be treated by first line

fluconazole141 As long as the yeast is identified as fluconazolesusceptible and the patient is stable fluconazole is indicated inneutropenic patients

Chronic disseminated candidiasis is mostly observed in neu-tropenic patients with haematological malignancies Its incidenceranges from 3 to 7 and is decreasing following the commonpractice of fluconazole as a prophylactic regimen in haematologypatients26142 The efficacy of fluconazole in that setting was evalu-ated only in observational or retrospective studies143144 Anaissieet al143 reported an 88 rate of cure in a series of 20 patients eitherresistant or intolerant to amphotericin B after prescription of flu-conazole (100ndash400 mgday median 30 weeks) Kauffman et al144

similarly reported 100 success in six patients resistant toamphotericin B (200ndash400 mgday for 2ndash14 months) Severalauthors believe that the daily dosage should be raised to 600ndash800 mgday145 In conclusion fluconazole cannot be used asfirst line treatment in the setting of systemic candidiasis amongneutropenic patients It is recommended when switching initialamphotericin B therapy to oral maintenance regimen if the patientwas not previously on fluconazole prophylaxis and was not knownto be colonizedinfected with a less-susceptible or resistant strainTreatment should be maintained for months until disappearance ofcalcification of the lesions especially if further antineoplasticdrugs courses have to be administered

Fluconazole in adult non-neutropenic patients with

candidaemia

Fluconazole has often been used for treatment of fungal infectionsin non-neutropenic patients (see Table 11) Early trials using flu-conazole looked at different doses A paper from the early 1990scompared doses of 5 mgkg versus 10 mgkg to treat candidiasis inICU patients The clinical response rate was better in the 10 mgkggroup and deaths were reduced in this group (24 versus 3) withfluconazole being well tolerated at both doses146 Six studiescompared the efficacy of fluconazole and amphotericin B innon-neutropenic patients with invasive candidiasis139140147ndash150

Of them three were randomized double-blind multicentrestudies140147148 All confirmed the similar efficacy of bothdrugs with better tolerance of the fluconazole regimen In 1994Rex et al148 compared in a randomized prospective multicentrestudy fluconazole (400 mgday) and amphotericin B (05ndash06 mgkgday) among 237 patients Both displayed the same clinical andmicrobiological efficacy and the same mortality rate at 2 weeksIn 1996 Anaissie et al140 performed in the same year a prospec-tive randomized multicentre study of 164 patients (including 104non-neutropenic patients) with more consistency in the fluconazoleand amphotericin B doses (fluconazole 400 mgday amphotericinB 25ndash50 mgday) Although clinical response rates were similarthere was significantly less toxicity in the fluconazole group Phi-lips et al147 in 1997 in a prospective randomized study confirmedthe pattern of efficacy (resolution of fungaemia and death at day14) of fluconazole (400 mgday) and amphotericin B (06 mgkgday) Other kinds of studies were also performed Nguyen et al150

in 1995 failed to find any difference of mortality between thefluconazole-treated (100ndash800 mgday) and amphotericin B-treatedgroups in an open prospective multicentre trial In 1996 Abele-Horn et al149 compared patients hospitalized in ICU treated eitherwith fluconazole (400 mgday on day 1 then 200 mgday) oramphotericin B (1ndash15 mgkgday) plus flucytosine in a random-ized prospective trial no difference in clinicalmicrobiological

Review

397

Table

10

Stu

die

so

nse

con

dar

yp

rop

hy

lact

icfl

uco

naz

ole

amo

ng

HIV

-in

fect

edp

atie

nts

Ref

eren

ceS

tud

yd

esig

nR

egim

en

Du

rati

on

of

trea

tmen

t

Nu

mb

er

of

pat

ien

tsR

ate

of

infe

ctio

ns

Lee

net

al

12

9R

D

B

SC

FL

Cp

o1

50

mg

wee

kv

ersu

sp

lace

bo

24

wee

ks

14

22

10

0

Ste

ven

set

al

13

0R

N

B

SC

FL

Cp

o2

00

mg

day

ver

sus

pla

ceb

o1

2w

eek

s1

20

13

62

Just

-Nu

bli

nget

al

13

1R

N

B

SC

FL

Cp

o5

0m

gd

ayo

r1

00

mg

day

6m

on

ths

18

11

ver

sus

pla

ceb

o1

92

1

21

95

Mar

rio

ttet

al

13

2R

D

B

PC

S

CF

LC

po

15

0m

gw

eek

ver

sus

pla

ceb

o6

mo

nth

s3

54

2

38

96

Sch

um

anet

al

13

3R

D

B

PC

M

CF

LC

20

0m

gw

eek

ver

sus

pla

ceb

o2

9m

on

ths

16

24

4

16

15

8

Hav

liret

al

13

4R

D

B

MC

FL

C4

00

mg

wee

kv

ersu

s2

00

mg

day

52

8d

ays

31

82

0

31

81

2

Pag

aniet

al

13

5R

D

B

PC

S

CF

LC

po

15

0m

gw

eek

ver

sus

pla

ceb

o3

7m

on

ths

67

71

61

71

90

(Plt00001)

Rr

andom

ized

DB

double

bli

ndP

Cp

lace

bo

contr

oll

edS

Cs

ingle

centr

eM

Cm

ult

icen

tre

FL

Cf

luco

naz

ole

poo

ral

OP

Co

rophar

yngea

lcan

did

iasi

sO

Co

eso

ph

agea

lcan

did

iasi

sV

alu

esg

iven

inb

old

face

are

stat

isti

call

ysi

gnif

ican

t

Review

398

Table

11

Stu

die

so

nfl

uco

naz

ole

ascu

rati

ve

trea

tmen

tam

on

gn

on

-neu

tro

pen

icp

atie

nts

Ref

eren

ceS

tud

yd

esig

nK

ind

of

infe

ctio

nR

egim

en

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

tsE

val

uat

ion

item

sE

ffic

acy

Ph

illi

pset

al

14

7R

M

C

PC

can

did

aem

iaF

LC

40

0m

gd

ayiv

ver

sus

AM

B

06

mg

kg

day

iv

4ndash

8w

eek

s5

0

53

clin

ical

mic

robio

logic

al

6m

on

ths

surv

ival

FL

C5

7

AM

B6

2

An

aiss

ieet

al

14

0R

M

C

PC

inv

asiv

e

can

did

iasi

s

FL

C4

00

mg

day

iv

ver

sus

AM

B

25

ndash5

0m

gd

ayiv

9d

ays

75

67

clin

ical

mic

robio

logic

alE

OT

FL

C66

AM

B6

4

An

aiss

ieet

al

13

9O

S

Cca

nd

idae

mia

FL

C2

00

ndash6

00

mg

day

ver

sus

AM

B

03

ndash1

2m

gk

gd

ay

13

day

s

10

day

s

45

45

clin

ical

mic

robio

logic

al

D0

D

5

EO

T

FL

C7

3

AM

B7

1

Ab

ele-

Ho

rnet

al

14

9R

S

Cin

vas

ive

can

did

iasi

s

FL

C2

00

mg

day

iv

ver

sus

AM

B1

ndash1

5m

gk

g

ever

yo

ther

day

+

5F

C3middot

25

gd

ay

14

day

s3

6

36

clin

ical

mic

robio

logic

alE

OT

FL

C64

AM

B+

5F

C6

3

Ng

uy

enet

al

15

0O

M

C

PC

can

did

aem

iaF

LC

10

0ndash

80

0m

gd

ay

ver

sus

AM

B

13

day

s6

7

22

7

dea

thE

OT

no

dif

fere

nce

inm

ort

alit

yat

D+

7D

+1

4

D+

21

Rex

etal

14

8R

D

B

MC

can

did

aem

iaF

LC

40

0m

gd

ayiv

ver

sus

AM

B

06

mg

kg

day

iv

4ndash

8w

eek

s1

03

10

3

clin

ical

mic

robio

logic

alW

12

FL

C70

AM

B7

9

Rr

and

om

ized

D

Bd

ou

ble

bli

nd

S

Bs

ing

leb

lin

dP

Cp

lace

bo

con

tro

lled

S

Cs

ing

lece

ntr

eM

Cm

ult

icen

tre

FL

Cf

luco

naz

ole

A

MB

am

ph

ote

rici

nB

5

FC

flu

cyto

sin

ep

oo

ral

Dd

ayW

wee

kE

OT

en

do

ftr

eatm

ent

iv

intr

aven

ou

s

Review

399

response or death could be found In 1996 Anaissie et al139 com-pared the same drugs in cancer patients with candidiasis andenrolled 90 patients Doses of both fluconazole and amphotericinwere highly variable (fluconazole 200ndash600 mgday amphotericinB 03ndash12 mgkgday) The two cohorts were well matched andresponse rates at day 5 for each cohort were similar overallresponse rates were slightly better for fluconazole and therewere significantly fewer toxic effects in the fluconazole group

A more recent comparison of fluconazole versus fluconazoleplus amphotericin B in non-neutropenic subjects compared 800mgday of fluconazole versus the same dose plus 07 mgkgdayof amphotericin B in a randomized blinded multicentre trial invol-ving 219 patients151 Success rates were slightly higher and therewas a faster clearance rate of candidaemia in the combination groupcompared with fluconazole alone This suggests that the two drugsare not antagonistic and may perhaps act synergistically

Although fluconazole may be the preferred agent in non-neu-tropenic patients because of its low toxicity the recent introductionof caspofungin challenges this place particularly as it has a broaderspectrum of action A randomized study comparing caspofunginversus amphotericin B for the treatment of candidaemia in bothneutropenic and non-neutropenic patients has been completed butthere is no direct comparison with fluconazole152 Results of aprospective randomized controlled multicentre trial comparinganidulafungin a new echinocandin and fluconazole in patientswith candidaemia should be available soon

Fluconazole for the treatment of specific Candida

organ infections

All randomized studies using fluconazole to date have been under-taken in oesophageal candidiasis or candidaemia none in Candidaorgan infection although some patients with invasive candidiasishave been included in the randomized studies Therefore the datapresented here come from non-comparative open-label studies

Osteoarticular infections due to Candida sp

Very few data are available on the efficacy of fluconazole as firstline therapy in osteoarticular infections due to Candida sp Someobservations associated with spondylodiscitis have been publishedand have been summarized in Table 12153ndash162 Fluconazole (200ndash400 mgday initially gt2 months) proved to be efficacious in threecases of knee infections due to C parapsilosis163ndash165 A prostheticjoint infection and osteomyelitis of the knee due toC albicanswerecured with high doses of 800 mgday of fluconazole for 2 months incombination with repeated surgical debridement after a 10 daycourse of fluconazole 400 mgday which seemed to be ineffi-cient166 Fluconazole (400ndash800 mgday for 6 months) was alsoeffective for the treatment ofC albicans post-surgical mediastinitisin two cases167168 Fluconazole (400 mgday for 7 months) suc-cessfully treated an old patient with acute myeloid leukaemia whopresented with C tropicalis arthritis of the knee169 The latestIDSA guidelines recommend surgical debridement and initialcourse of amphotericin B for 2ndash3 weeks followed by fluconazolefor a total duration of 6ndash12 months57

Endophthalmitis due to Candida sp

A combination of partial or complete vitrectomy intraocularamphotericin B and antifungal drugs is the usual therapeuticapproach to Candida sp eye infections Several documented T

able

12

Rep

ort

so

fp

atie

nts

wit

hsp

on

dy

lod

isci

tis

du

eto

Candida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Lo

cali

zati

on

of

infe

ctio

n

Candida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Do

seo

ffl

uco

naz

ole

(mg

day

)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y

(fo

llo

w-u

pd

ura

tio

n)

Gar

bin

oet

al

16

2lu

mb

arCalbicans

14

00

3m

on

ths

(rel

apse

)

then

6m

on

ths

ndashre

cov

ery

(16

mo

nth

s)

lum

bar

Ctropicalis

18

00

foll

ow

edb

yit

raco

naz

ole

reco

ver

y(4

mo

nth

s)

Ser

aval

liet

al

16

1lu

mb

arCglabrata

18

00

3w

eek

sre

pla

ced

by

AM

B(7

0d

ays)

then

lip

idco

mp

lex

(56

day

s)

fail

ure

wit

hfl

uco

naz

ole

then

reco

ver

y(1

6m

on

ths)

El-

Zaa

tariet

al

16

0d

ors

alCalbicans

14

00

3m

on

ths

ndashre

cov

ery

(1y

ear)

Tu

rner

etal

15

9d

ors

o-l

um

bar

Calbicans

12

00

(1m

on

th)

then

10

01

2m

on

ths

afte

rfa

ilu

reo

fA

MB

li

po

som

al

AM

Ban

d5

FC

(9w

eek

s)

reco

ver

y(3

yea

rs)

Ro

ssel

etal

15

8d

ors

alCalbicans

14

00

(14

day

s)th

en2

00

7m

on

ths

afte

rfa

ilu

reo

fA

MB

(21

day

s)re

cov

ery

(1y

ear)

Jon

nal

agad

daet

al

15

7d

ors

alCalbicans

12

00

6m

on

ths

AM

B(3

g)

+5

FC

reco

ver

y(8

mo

nth

s)

Hen

neq

uin

etal

15

6lu

mb

arCalbicans

14

00

6m

on

ths

ndashre

cov

ery

(47

mo

nth

s)

lum

bar

C

alb

ican

s1

20

06

mo

nth

sndash

reco

ver

y(1

7m

on

ths)

Laf

on

tet

al

15

5lu

mb

arCalbicans

14

00

4w

eek

sndash

reco

ver

y(1

8m

on

ths)

Tan

get

al

15

4d

ors

alCalbicans

12

00

1y

ear

ndashre

cov

ery

(16

mo

nth

s)

Su

gar

etal

15

3d

ors

alan

dlu

mb

arCtropicalis

11

00

ndash1

50

1y

ear

AM

B(3

80

mg

)re

cov

ery

(26

mo

nth

s)

AM

B

amphote

rici

nB

5F

C

flucy

tosi

ne

Review

400

clinical cases reported the efficacy of fluconazole alone or incombination with other treatments in cases of endophthalmitisdue to Candida spp16170ndash173 Finally several recent series con-firmed fluconazole efficacy in cases of severe ocular infectionsdue to susceptible Candida sp in non-neutropenic patients174ndash180

Their results are summarized in Table 13 Most cases are due toC albicans and fluconazole-resistant species causing endoph-thalmitis is extremely rare On the basis of these data the IDSArecommends the use of fluconazole in this indication particularlyas follow-up therapy58

Meningitis due to Candida sp

Very few data exist on fluconazolersquos efficacy for the initial treat-ment of Candida sp meningitis in adults although this drug has avery good CSF penetration Oral fluconazole (800 mgday for3 months then 200 mgday) was successful for the treatment ofa C albicans meningitis in an HIV-infected patient with a CD4 cellcount of 35 cellsmm3 who refused intravenous therapy181

Endocarditis due to Candida sp

No series has documented the efficacy of fluconazole in endocard-itis due to Candida sp Only a few clinical cases have been pub-lished and most of these are summarized in Table 14182ndash198 Thesecases illustrate the efficacy of fluconazole (sometimes with nosurgical treatment) in endocarditis due to C albicans and alsoin endocarditis related to some non-albicans Candida spp espe-cially C parapsilosis However no study has demonstrated thesuperiority of fluconazole over amphotericin B in this indicationand there are insufficient data to recommend fluconazole as the firstline treatment for endocarditis due to Candida spp58199 Theechinocandins might have a place as primary therapy in thesecases Fluconazole (200ndash400 mgday) is often employed as partof a long-term suppressive regimen especially if valve replacementis not possible because of the high propensity for delayed relapse ofcandidal endocarditis200201

Peritonitis due to Candida sp

Peritonitis due to Candida sp may develop in patients with peri-toneal dialysis catheters or in those with surgical or traumaticinjury to the gut wall In this latter situation Candida spp areusually part of a polymicrobial infection Isolation of Candidaby direct examination of peritoneal fluid is an independent factorfor a severe outcome202 and recent small studies suggest thatprompt effective adequate and safe antifungal therapy shouldbe given in all cases of Candida sp peritonitis in order to lowerthe mortality rate and shorten the hospital stay113116 In a recentstudy of 23 cases secondary to peptic ulcer perforation the mor-tality rate in patients receiving fluconazole (200 mg intravenouslytwice daily for 2ndash4 weeks) was high (five of eight cases) probablyrelated to inadequate or too late initiation of antifungal therapy203

Some cases showing fluconazole efficacy have been reported inpatients with continuous ambulatory peritoneal dialysis eitheralone or in combination with flucytosine204ndash207 Catheter removalis crucial in these cases

Urinary infections due to Candida spp

Candida is by far the most frequent agent of urinary fungal infec-tions The line between colonization and real infection is generallyblurred Candiduria usually present as nosocomial infections T

able

13

Rep

ort

so

fp

atie

nts

wit

hen

do

ph

thal

mit

isd

ue

toCandida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Met

ho

do

log

y

of

stu

dy

Candida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Do

seo

f

flu

con

azo

le(m

gd

ay)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y

(fo

llo

w-u

pd

ura

tio

n)

Mar

tin

ez-V

azq

uez

etal

18

0p

rosp

ecti

ve

Calbicans

11

40

02

ndash8

wee

ks

AM

Biv

(n=

9)

or

no

trea

tmen

t(n

=1

)u

nti

l

vit

rect

om

y(n

=1

0

2ndash

18

0

day

saf

ter

dia

gn

osi

s)

91

1(6

mo

nth

s)

Ess

man

etal

17

9re

tro

spec

tiv

eCalbicansCtropicalis

5u

nsp

ecif

ied

un

spec

ifie

dv

itre

cto

myndash

loca

lA

MB

55

(25

ndash1

15

mo

nth

s)

Ch

rist

mas

etal

17

8p

rosp

ecti

ve

CalbicansCtropicalis

51

00

ndash2

00

3ndash

6w

eek

sv

itre

cto

my

55

(4ndash

11

mo

nth

s)

Ak

leret

al

17

7re

tro

spec

tiv

eu

nsp

ecif

ied

6to

tal

med

ian

do

se

=9

97

5m

g

med

ian

=5

2d

ays

AM

Biv

lt5

00

mg

+

vit

rect

om

y

1

56

re

lap

se

1(pound

6w

eek

s)

Lu

ttru

llet

al

17

6re

tro

spec

tiv

eCalbicans

(n=

2)

un

spec

ifie

d(n

=2

)

42

00

ndash4

00

4w

eek

s(n

=3

)v

itre

cto

my

1

44

(3ndash

25

mo

nth

sn

=3

)

del

Pal

acio

etal

17

5re

tro

spec

tiv

eCalbicans

74

00

(1d

ay)

then

20

03

wee

ks

ndash6

7(v

itre

cto

my

refu

sal

in

1p

atie

nt)

(Dagger6

mo

nth

s)

Kau

ffm

anet

al

17

4re

tro

spec

tiv

e

len

sim

pla

nts

Cparapsilosis

44

00

(20

0in

pat

ien

ts

wit

hre

nal

fail

ure

)

1y

ear

fail

ure

of

loca

lA

MB

rela

pse

ifn

ole

ns

abla

tio

n

(2y

ears

afte

rst

op

pin

g)

AM

B

amphote

rici

nB

iv

in

trav

enous

Review

401

Table

14

Rep

ort

so

fp

atie

nts

wit

hen

do

card

itis

du

eto

Candida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Val

vu

lar

inv

olv

emen

tCandida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Dose

of

fluco

naz

ole

(mg

day

)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y(f

oll

ow

-up

du

rati

on

)

Ino

ueet

al

18

2ao

rtic

val

ve

Cparapsilosis

16

00

then

40

01

8m

on

ths

surg

ery

reco

ver

y(1

8m

on

ths)

Lej

ko

-Zu

pan

cet

al

19

7m

itra

lp

rost

hes

isCparapsilosis

14

00

(14

day

s)th

en1

00

8m

on

ths

AM

B(3

9g

)A

BC

D

(15

g)

no

rep

lace

men

t

reco

ver

y(gt

3y

ears

)

Joly

etal

19

8p

acem

aker

Calbicans

14

00

(6d

ays)

then

20

07

mo

nth

ssu

rger

yre

cov

ery

(18

mo

nth

s)

Ng

uy

enet

al

19

6ao

rtic

pro

sth

esis

Calbicans

14

00

then

20

04

5y

ears

AM

B+

5F

C

12

wee

ks

no

rep

lace

men

t

reco

ver

y(5

5y

ears

)

Gil

ber

tet

al

19

5ao

rtic

pro

sth

esis

Calbicans

12

00

8m

on

ths

surg

ery

AM

B(2

g)

+

5F

C

40

day

s

reco

ver

y(9

mo

nth

s)

Wel

lset

al

19

4m

itra

lan

dtr

icu

spid

val

ves

Calbicans

12

00

ndash4

00

(14

day

s)

then

40

0th

en5

0

65

mo

nth

s

(40

0m

g)

and

10

mo

nth

s

(50

mg

)

no

rep

lace

men

tre

cov

ery

(45

yea

rs)

Zah

idet

al

19

3m

itra

lv

alv

e

(pro

bab

le)

Cparapsilosis

14

00

18

mo

nth

sA

MB

(5g

)+

5F

C

ket

oco

naz

ole

(80

0m

gd

ay

4m

on

ths)

no

rep

lace

men

t

reco

ver

y(5

yea

rs)

Can

cela

set

al

19

2m

itra

lv

alv

eCparapsilosis

12

00

4m

on

ths

surg

ery

A

MB

(2g

)re

cov

ery

(4m

on

ths)

Th

aku

ret

al

19

1ao

rtic

pro

sth

esis

Calbicans

12

00

6w

eek

sA

MB

(30

mg

day

)

6w

eeks

no

repla

cem

ent

reco

ver

y(2

6m

on

ths)

Czw

erw

iecet

al

19

0ao

rtic

pro

sth

esis

Cparapsilosis

14

00

26

mo

nth

sA

MB

(72

5m

g)

no

rep

lace

men

t

reco

ver

y(2

6m

on

ths)

Ota

kiet

al

18

9m

itra

lp

rost

hes

isCparapsilosis

1u

nsp

ecif

ied

68

day

sn

ore

pla

cem

ent

fail

ure

(dea

thd

ue

toce

reb

ral

hae

mo

rrh

age

and

fev

er)

Wal

lbri

dg

eet

al

18

8m

itra

lp

rost

hes

isCparapsilosis

12

00

-40

0gt

7w

eek

sA

MB

(30

0m

g)

no

rep

lace

men

t

reco

ver

y(6

mo

nth

s)

Ven

dit

tiet

al

18

7in

tera

tria

lse

ptu

mCalbicans

12

00

(28

day

s)th

en6

00

(11

day

s)th

en4

00

6m

on

ths

no

rep

lace

men

tre

cov

ery

(14

mo

nth

s)

Her

nan

dez

etal

18

6m

itra

lv

alv

eCalbicans

12

00

3m

on

ths

AM

Bfa

ilu

ren

o

rep

lace

men

t

imp

rov

emen

t(3

mo

nth

s)

Ro

up

ieet

al

18

5ao

rtic

val

ve

Ctropicalis

14

00

50

day

sn

ore

pla

cem

ent

reco

ver

y(1

1m

on

ths)

Mar

tin

oet

al

18

4in

tera

tria

lse

ptu

mCparapsilosis

13

mg

kg

(7d

ays)

then

6m

gk

g

gt3

mo

nth

sG

M-C

SF

(gt6

wee

ks)

no

rep

lace

men

t

reco

ver

y(5

mo

nth

s)

Isal

skaet

al

18

3m

itra

lp

rost

hes

isCparapsilosis

11

00

ndash2

00

11

mo

nth

sn

ore

pla

cem

ent

reco

ver

y(1

yea

r)

AM

B

amph

ote

rici

nB

5

FC

fl

ucy

tosi

ne

AB

CD

am

ph

ote

rici

nB

coll

oid

ald

isp

ersi

on

G

M-C

SF

g

ran

ulo

cyte

ndashm

on

ocy

teco

lon

y-s

tim

ula

tin

gfa

cto

r

Review

402

favoured by indwelling urinary catheters immunosuppressivedrugs or antibiotic prescriptions diabetes mellitus and extremeages C albicans is involved in half of the cases followed byC glabrata in 15 of the cases In 10 of cases infection involvesmore than one species208 Fluconazole achieves a 10 times higherconcentration in urine than in blood with powerful effect even onCglabrata infections Therefore it represents a first line treatment ofany Candida urinary tract infection

In a randomized placebo-controlled multicentre study amongpatients with asymptomatic candiduria Sobel et al209 found thatfluconazole (200 mgday) hastened the time to negative resultsof urine cultures However the rate of negative urine cultures2 weeks after the end of therapy was similar in the fluconazole-and placebo-treated groups showing the minimal utility of treat-ment in that setting Indeed asymptomatic candiduria should betreated only in high-risk situations namely patients with neutrope-nia infants with low birth weight patients with renal allografts andpatients who will undergo urologic manipulations (recommenda-tion of grade B-III from the IDSA) The optimal regimen in thatsetting is not known Short courses regimen are not recommendedand therapy for 1ndash2 weeks should be efficient

Ascending pyelonephritis treatment should also include ade-quate urinary drainage and removal of obstructive fungusballs210 Urinary tract devices should be optimally removed orat least replaced

Haematogenous renal involvement should be treated with high-dose parenteral fluconazole (6 mgkgday) in accordance with therecently published IDSA guidelines57

Fluconazole in childreninfants

No specific approval of fluconazole has been obtained inyoung children before the age of 6 months but a few studieshave evaluated its use in several settings

Prophylaxis of systemic candidiasis in neonates

Few studies have focused on the use of fluconazole as a prophy-lactic agent against invasive candidiasis in neonates Kaufmanet al211 demonstrated in 2001 the efficacy and safety of flucona-zole (3 mgkg every 3 days during the first 2 weeks then every2 days during the following 2 weeks and then every day until thesixth week of life) in extremely low birth weight and high-riskinfants (lt1000 g) in preventing both colonization and invasivefungal infection High risk was defined as the presence of a centralvascular catheter or endotracheal tube Indeed among the 50infants randomly assigned to fluconazole the rate of colonization(22) was significantly lower than in the 50 placebo-treated ones(60) no invasive fungal infection developed in the fluconazolegroup compared with a 20 rate of infection in the placebo groupNo adverse effect of fluconazole was documented

Kicklighter et al212 similarly observed the safety of fluconazoleat 6 mgkg (for 6 weeks) and its efficacy among neonates with lowbirth weight (lt1500 g) in the prevention of rectal colonization(however occurrence of invasive candidiasis was similar inboth groups) A Cochrane review of fluconazole prophylaxis inpreterm infants demonstrated a reduced risk of invasive infection(related risk 020) and mortality (related risk 044) in fluconazole-treated patients compared with placebo-treated patients213

Although concerns about resistance to azoles have been raised

the vast majority ofCandida spp strains have remained susceptibleto fluconazole over the past decade in this population40

Fluconazole in systemic candidiasis in childreninfants

Neonatal candidaemia Candidaemia is a major cause of sepsis inneonatal ICU representing up to 16 of all sepsis cases Therelated mortality rate is high often nearly 50214 Most casesare related to C albicans and C parapsilosis with a recent risein cases related to C tropicalis The main risk factors for invasivecandidiasis among neonates are low birth weight intravascularcatheters intratracheal intubation total parenteral nutrition andadministration of intralipid solution and recent administration ofbroad-spectrum antibiotics and corticosteroids10

Treatment with amphotericin B and 5-flucytosine has been thegold standard for years However amphotericin B has some seriousside effects which makes it mandatory to consider its use in thatsetting With good profile of tolerance good diffusion in all tissuesand body fluids and reliable oral absorption fluconazole has beenstudied as an alternative (see Table 15) In 1994 Fasano et al215

reported the compassionate use of fluconazole among 40 new-borns including 11 who presented with Candida sp meningitisThey were treated with a mean daily dosage of 5 mgkgday for amean duration of 26 days Of the 32 patients with evaluable out-come 31 experienced clearance of infection Other studies haveconfirmed these results in the recent years11216ndash220 In a multicen-tre prospective randomized study Driessen et al220 compared theefficacy and safety of either amphotericin B ndash 5-flucytosine orfluconazole (oral or intravenous dose of 10 mgkg as initialdose and then 5 mgkgday) in neonates with candidaemia Inthe fluconazole group 812 (67) survived versus 611 (55) inthe other group220 Among the four patients who died in the flu-conazole group two had treatment failure versus one in the ampho-tericin B group Cytolytic hepatitis was less frequent in thefluconazole-treated group Two isolated case reports also suggestthat the association of fluconazole and flucytosine might be syn-ergistic in the treatment of neonatal candidaemia222223

Very recently Mondal et al229 compared the efficacy and safetyof oral itraconazole versus oral fluconazole (both doses of 10 mgkgday) in newborns and paediatric patients with candidaemiaSimilar cure rate (81 and 82) mortality rate (95 and 135)and number of side effects were observed224 Fluconazole thusappears as a safe and effective systemic antifungal agent in thesetting of neonatal candidiasis

Children with systemic candidiasis Excluding the setting of neo-natal candidiasis very few studies have however focused on thepaediatric population when studying the efficiency of fluconazolefor the treatment of invasive candidiasis

In 1991 Viscoli et al reported the outcome of 24 immunocom-promised children treated with fluconazole (6 mgkgday) for 34episodes of proven invasive candidiasis A total of 3034 clinicaland microbiological cures were achieved Two patients with fun-gaemia due toC parapsilosis required an increase in dosage of up to12 mgkg Transient drug-related increases of liver transaminasesoccurred in two cases (6)225 In 1994 Fasano et al reported theoutcome of 63 children with AIDS cancer or transplantationprospectively receiving fluconazole as compassionate treatment(dose regimen ranging from 016 to 11 mgkgday mean 34 mgkgday)215 Half of them had fungaemia while the others hadrespiratory urinary tract or superficial oropharyngeal infections

Review

403

Clinical cure or improvement was achieved in 5263 (83) andpathogen eradication was achieved in 4359 (73)17 Huttovaet al218 reported in 1998 the outcome of 10 children withnosocomial fungal meningitis including 8 cases of candidal men-ingitis treated using fluconazole Five of them survived with clinicaland microbiological cure

Conclusions

Almost 15 years after its launch fluconazole remains a cornerstoneof antifungal prophylaxis and therapy of invasive candidiasis It hasan excellent pharmacokinetic and safety profile even in debilitatedpatients with good tissue penetration and a lack of major druginteractions particularly with immunosuppressive agents It can beprescribed in patients with renal failure if daily dosages are adaptedto the creatinine serum level Its spectrum of antimicrobial efficacyis reasonable and it remains active against most intrinsically sus-ceptible Candida spp encountered in systemic disease with lt5of C albicans resistant to fluconazole in that setting Although Ckrusei is intrinsically resistant to fluconazole it is rarely reported asa cause of systemic infection outside neutropenic patients Thus Cglabrata is the only species which might now limit the use offluconazole for the first line therapy of yeast fungaemia whenthe species is not identified Similarly patients who recentlyreceived fluconazole as antifungal prophylaxis should not be trea-ted with fluconazole for the curative treatment of a presumed orproven episode of systemic candidiasis The fungistatic effect offluconazole against Candida spp does not appear to influence theoutcome of candidaemic episodes at least in comparison withamphotericin B which is apparently fungicidal against Candidaspp Finally when summarizing its valuable properties the strongdemonstration of its efficacy in large randomized controlled trialsand selected clinical series its availability in various commercialpresentations and its current low cost fluconazole still remains aleading antifungal drug against susceptible Candida species

Transparency declarations

C C E H A L P R and F D have no conflicts to declareD W D In the past 5 years D W D has received grant supportfrom Astellas Merck Pfizer F2G OrthoBiotech Indevus Basileathe Fungal Research Trust the Wellcome Trust the National Insti-tute of Allergy and Infectious Diseases and the European Union Hehas been an advisorconsultant to Merck Basilea Vicuron (nowPfizer) Schering Plough Indevus F2G Nektar Daiichi SigmaTau Astellas PPL Therapeutics and Uriach He has been paid fortalks on behalf of Astellas Merck and Pfizer He holds foundershares in F2G Ltd and GBE Diagnostics Ltd and talks on behalf ofAstellas Merck and Gilead Sciences O L Speakers bureau forPfizer

References

1 Richardson K The discovery and profile of fluconazole J Chemo-

ther 1990 2 51ndash4

2 Richardson K Brammer KW Marriott MS et al Activity of

UK-49858 a bis-triazole derivative against experimental infections

with Candida albicans and Trichophyton mentagrophytes Antimicrob

Agents Chemother 1985 27 832ndash5

3 Vanrsquot Wout JW Mattie H van Furth R A prospective study of the

efficacyof fluconazole (UK-49858)againstdeep-seated fungal infections

J Antimicrob Chemother 1988 21 665ndash72Table

15

No

n-c

om

par

ativ

est

ud

ies

on

flu

con

azo

leas

cura

tiv

etr

eatm

ent

of

neo

nat

alca

nd

idae

mia

Ref

eren

ce

Nu

mb

ero

f

pat

ien

tsR

egim

enM

icro

bio

log

ical

cure

Sid

eef

fect

s

Dri

esse

net

al

22

02

1v

ery

low

bir

thw

eig

ht

5m

gk

gfo

r

1ndash

42

day

sm

ean

16

90

3

0

cyto

lyti

ch

epat

itis

Fas

anoet

al

21

54

05

mg

kg

for

2ndash

80

day

sm

ean

26

97

5

cy

toly

tic

hep

atit

is

Wai

ner

etal

21

61

91

0m

gk

go

nd

ay1

then

5m

gk

g

63

su

rviv

ing

32

fun

gal

free

dea

ths

NS

Hu

anget

al

21

71

8v

ery

low

bir

thw

eig

ht

3ndash

10

mg

kg

for

15

ndash1

73

day

sm

ean

34

6fi

rst

lin

etr

eatm

ent

83

13

afte

rA

MB

fail

ure

6

2

29

cy

toly

tic

hep

atit

is

Hu

tto

vaet

al

21

84

0v

ery

low

bir

thw

eig

ht

6m

gk

gfo

r6

ndash4

8d

ays

65

cu

rew

ith

ou

tre

lap

se5

cy

toly

tic

hep

atit

is

5

-ele

vat

edse

rum

crea

tin

ine

Gu

rpin

aret

al

21

92

42

ndash1

6m

gk

gfo

r

5ndash

72

day

sm

ean

25

96

8

an

aem

iao

rcy

toly

tic

hep

atit

is

Sch

war

zeet

al

11

53

5ndash

6m

gk

gfo

r3

wee

ks

mea

n2

17

8

4

cyto

lyti

ch

epat

itis

AM

B

amphote

rici

nB

ver

ylo

wbir

thw

eight

lt1500

g

NS

st

atis

tica

lly

not

signif

ican

t

Review

404

4 Vanrsquot Wout JW deGraeff-Meeder ER Paul LC et al Treatment of

two cases of cryptococcal meningitis with fluconazole Scand J Infect Dis

1988 20 193ndash8

5 Tucker RM Williams PL Arathoon EG et al Pharmacokinetics of

fluconazole in cerebrospinal fluid and serum in human coccidioidal

meningitis Antimicrob Agents Chemother 1988 32 369ndash73

6 ByrneWRWajszczukCPCryptococcalmeningitis in theacquired

immunodeficiency syndrome (AIDS) successful treatment with flucona-

zole after failure of amphotericin B Ann Intern Med 1988 108 384ndash5

7 HughesCE BeggsWH Action of fluconazole (UK-49858) in rela-

tion to other systemic antifungal azoles J Antimicrob Chemother 1987

19 171ndash4

8 DebruyneDClinicalpharmacokineticsof fluconazole insuperficial

and systemic mycoses Clin Pharmacokinet 1997 33 52ndash77

9 Brammer KW Coates PE Pharmacokinetics of fluconazole in

pediatric patients Eur J Clin Microbiol Infect Dis 1994 13 325ndash9

10 Schwarze R Penk A Pittrow L Administration of fluconazole in

children below 1 year of age Mycoses 1999 42 3ndash16

11 Schwarze R Penk A Pittrow L Treatment of candidal infections

with fluconazole in neonates and infants Eur J Med Res 2000 5 203ndash8

12 Thaler FBernardBTodMet al Fluconazolepenetration in cereb-

ral parenchyma in humans at steady stateAntimicrob Agents Chemother

1995 5 1154ndash6

13 Bozzette SA Gordon RL Yen A et al Biliary concentrations of

fluconazole in a patient with candidal cholecystitis case reportClin Infect

Dis 1992 4 701ndash3

14 Debruyne D Ryckelynck JP Moulin M et al Pharmacokinetics of

fluconazole in patients undergoing continuous ambulatory peritoneal dial-

ysis Clin Pharmacokinet 1990 18 491ndash8

15 Tod M Lortholary O Padoin C et al Intravenous penetration of

fluconazole during endophthalmitis Clin Microbiol Infect 1997 3 143ndash4

16 Urbak SF Degn T Fluconazole in the management of fungal ocu-

lar infections Ophthalmologica 1994 3 147ndash56

17 Fasano C OrsquoKeefe J Gibbs D Fluconazole treatment of children

with severe fungal infections not treatable with conventional agentsEur J

Clin Microbiol Infect Dis 1994 13 344ndash7

18 Aleck KA Bartley DL Multiple malformation syndrome following

fluconazole use in pregnancy report of an additional patient Am J Med

Genet 1997 72 253ndash6

19 Buijk SL Gyssens IC Mouton JW et al Pharmacokinetics of

sequential intravenous and enteral fluconazole in critically ill surgical

patients with invasive mycoses and compromised gastro-intestinal func-

tion Intensive Care Med 2001 27 115ndash21

20 El-Yazigi AEllisMErnstPet al Pharmacokinetics of oral flucona-

zole when used for prophylaxis in bone marrow transplant recipients

Antimicrob Agents Chemother 1997 41 914ndash17

21 Finch CK Green CA Self TH Fluconazole-carbamazepine inter-

action South Med J 2002 95 1099ndash100

22 Tucker RM Denning DW Hanson RH et al Interaction of azoles

with rifampin phenytoin and carbamazepine in vitro and clinical obser-

vations Clin Infect Dis 1992 14 165ndash74

23 Stockley IH Stockleyrsquos Drug Interactions A Source Book of Inter-

actions Their Mechanisms Clinical Importance and Management 6th

edn London UK Pharmaceutical Press 2002

24 von Moltke LL Greenblatt DJ Duan SX et al Inhibition of terfena-

dine metabolism in vitro by azole antifungal agents and by selective sero-

tonin reuptake inhibitor antidepressants relation to pharmacokinetic

interactions in vivo J Clin Psychopharmacol 1996 16 104ndash12

25 BrockmeyerNH Tillmann I Mertins L et al Pharmacokinetic inter-

action of fluconazole and zidovudine in HIV-positive patients Eur J Med

Res 1997 2 377ndash83

26 van Burik JA LeisenringW Myerson D et al The effect of prophy-

lactic fluconazole on the clinical spectrum of fungal diseases in bone

marrow transplant recipients with special attention to hepatic candidiasis

An autopsy study of 355 patients Medicine 1998 77 246ndash54

27 Wingard JR Antifungal chemoprophylaxis after blood andmarrow

transplantation Clin Infect Dis 2002 34 1386ndash90

28 GarbinoJLewDPRomandJAetalPreventionofsevereCandida

infections in nonneutropenic high-risk critically ill patients a randomized

double-blind placebo-controlled trial in patients treatedbyselectivediges-

tive decontamination Intensive Care Med 2002 28 1708ndash17

29 Gearhart MO Worsening of liver function with fluconazole and

review of azole antifungal hepatotoxicity Ann Pharmacother 1994 281177ndash81

30 Crerar-Gilbert A Boots R Fraenkel D et al Survival following ful-

minant hepatic failure from fluconazole induced hepatitis Anaesth Inten-

sive Care 1999 27 650ndash2

31 PappasPGKauffmanCAPerfect Jetal Alopeciaassociatedwith

fluconazole therapy Ann Intern Med 1995 123 354ndash7

32 Stevens DA Diaz M Negroni R et al Safety evaluation of chronic

fluconazole therapy Fluconazole Pan-American Study Group

Chemotherapy 1997 5 371ndash7

33 Anaissie EJ Kontoyiannis DP Huls C et al Safety plasma con-

centrations and efficacy of high-dose fluconazole in invasive mold infec-

tions J Infect Dis 1995 172 599ndash602

34 Gussenhoven MJ Haak A Peereboom-Wynia JD et al Stevens-

Johnson syndrome after fluconazole Lancet 1991 338 120

35 NovelliVHolzelHSafetyand tolerabilityof fluconazole inchildrenAntimicrob Agents Chemother 1999 43 1955ndash60

36 Koks CH Crommentuyn KM Hoetelmans RM et al Can

fluconazole concentrations in saliva be used for therapeutic drug mon-

itoring Ther Drug Monit 2001 4 449ndash53

37 Louie A Drusano GL Banerjee P et al Pharmacodynamics of

fluconazole in amurinemodel of systemic candidiasisAntimicrob Agents

Chemother 1998 42 1105ndash9

38 PittrowLPenkAPlasmaand tissueconcentrationsof fluconazole

and their correlation to breakpoints Mycoses 1997 40 25ndash32

39 Rex JH Pfaller MA Galgiani JN et al Development of interpretive

breakpoints forantifungalsusceptibility testing conceptual frameworkand

analysis of in vitro-in vivo correlation data for fluconazole itraconazole

and Candida infections Subcommittee on Antifungal Susceptibility Test-

ingof theNationalCommittee forClinical LaboratoryStandardsClin Infect

Dis 1997 24 235ndash47

40 Pfaller MA Diekema DJ Twelve years of fluconazole in clinical

practiceglobal trends inspeciesdistributionand fluconazolesusceptibility

of bloodstream isolatesofCandida International FungalSurveillancePar-

ticipant Group Clin Microbiol Infect 2004 10 Suppl 1 11ndash23

41 Tortorano AM Rigoni AL Biraghi E et al The European Confed-

eration of Medical Mycology (ECMM) survey of candidaemia in Italy anti-

fungal susceptibility patterns of 261 non-albicans Candida isolates from

blood J Antimicrob Chemother 2003 52 679ndash82

42 Pfaller MAMesser SA Boyken L et al Geographic variation in the

susceptibilities of invasive isolates of Candida glabrata to seven systemi-

cally active antifungal agents a global assessment from the ARTEMIS

Antifungal Surveillance Program conducted in 2001 and 2002 J Clin

Microbiol 2004 42 3142ndash6

43 Paya CV Fungal infections in solid-organ transplantation Clin

Infect Dis 1993 16 677ndash88

44 Singh N Wagener MM Marino IR et al Trends in invasive fungal

infections in liver transplant recipients correlation with evolution in trans-

plantation practices Transplantation 2002 73 63ndash7

45 Fung JJ Fungal infection in liver transplantation Transplant InfectDis 2002 4 18ndash23

46 Winston DJ Pakrasi A Busuttil RW Prophylactic fluconazole in

liver transplant recipientsA randomized double-blind placebo-controlled

trial Ann Intern Med 1999 131 729ndash37

47 Gladdy RA Richardson SE Davies HD et al Candida infection in

pediatric liver transplant recipients Liver Transpl Surg 1999 5 16ndash24

Review

405

48 Castaldo P Stratta RJ Wood RP et al Clinical spectrum of fungal

infections after orthotopic liver transplantation Arch Surg 1991 126149ndash56

49 Husain S Tollemar J Dominguez EA et al Changes in the spec-

trum and risk factors for invasive candidiasis in liver transplant recipients

prospective multicenter case-controlled study Transplantation 2003

75 2023ndash9

50 GeorgeMJ Snydman DRWerner BG et al The independent role

of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic

liver transplant recipients Boston Center for Liver Transplantation

CMVIG-Study Group Cytogam MedImmune Inc Gaithersburg Mary-

land Am J Med 1997 103 106ndash13

51 Dockrell DH Mendez JC Jones M et al Human herpesvirus 6

seronegativity before transplantation predicts the occurrence of fungal

infection in liver transplant recipientsTransplantation 1999 67 399ndash403

52 Tollemar J Ericzon BG Barkholt L et al Risk factors for deep

Candida infections in liver transplant recipients Transplant Proc 1990

22 1826ndash7

53 Lumbreras C Cuervas-Mons V Jara P et al Randomized trial of

fluconazole versus nystatin for the prophylaxis of Candida infection

following liver transplantation J Infect Dis 1996 174 583ndash8

54 Winston DJ Busuttil RW Randomized controlled trial of oral itra-

conazole solution versus intravenousoral fluconazole for prevention of

fungal infections in liver transplant recipients Transplantation 2002

74 688ndash95

55 Tortorano AM Viviani MA PaganoA et al Candida colonization in

orthotopic liver tranplantation fuconazole versus oral amphoericin B

J Mycol Med 1995 5 21ndash4

56 Kung N Fisher N Gunson B et al Fluconazole prophylaxis for

high-risk liver transplant recipients Lancet 1995 345 1234ndash5

57 Pappas PG Rex JH Sobel JD et al Guidelines for treatment of

candidiasis Clin Infect Dis 2004 38 161ndash89

58 PayaCV Prevention of fungal infection in transplantation TransplInfect Dis 2002 4 S46ndash51

59 LortholaryO Dupont B Antifungal prophylaxis during neutropenia

and immunodeficiency Clin Microbiol Rev 1997 10 477ndash504

60 Benedetti E Gruessner AC Troppmann C et al Intra-abdominal

fungal infections after pancreatic transplantation incidence treatment

and outcome J Am Coll Surg 1996 183 307ndash16

61 LumbrerasC Fernandez I Velosa J et al Infectious complications

following pancreatic transplantation incidence microbiological and clini-

cal characteristics and outcome Clin Infect Dis 1995 20 514ndash20

62 Patterson JE Epidemiology of fungal infections in solid organ

transplant patients Transpl Infect Dis 1999 1 229ndash36

63 Kusne S Furukawa H Abu-Elmagd K et al Infectious complica-

tions after small bowel transplantation in adults an update Transplant

Proc 1996 28 2761ndash2

64 Paterson DL Ndirangu M Kwak EJ et al Opportunistic infections

in solid-organ transplant recipients pre-treated with alumetuzumab In

Abstracts of the Forty-Fourth Interscience Conference on Antimicrobial

Agents and Chemotherapy Washington DC 2004 Abstract K-1427 p

357 American Society for Microbiology Washington DC USA

65 Kramer MR Marshall SE Starnes VA et al Infectious complica-

tions in heart-lung transplantation Analysis of 200 episodes Arch Intern

Med 1993 153 2010ndash6

66 Goodrich JMReedECMori M et al Clinical features and analysis

of risk factors for invasive candidal infection after marrow transplantation

J Infect Dis 1991 164 731ndash40

67 Dykewicz CA Centers for Disease Control and Prevention (US)

Infectious Diseases Society of America American Society of Blood and

MarrowTransplantation Summary of the guidelines for preventing oppor-

tunistic infections among hematopoietic stem cell transplant recipients

Clin Infect Dis 2001 33 139ndash44

68 Sable CA Donowitz GR Infections in bone marrow transplant

recipients Clin Infect Dis 1994 18 273ndash81

69 Goodman JLWinston DJ Greenfield RA et al A controlled trial of

fluconazole to prevent fungal infections in patients undergoing bone mar-

row transplantation N Engl J Med 1992 326 845ndash51

70 Slavin MA Osborne B Adams R et al Efficacy and safety of flu-

conazole prophylaxis for fungal infectionsaftermarrow transplantationmdasha

prospective randomized double-blind study J Infect Dis 1995 1711545ndash52

71 Marr KA Seidel K SlavinMA et al Prolonged fluconazole prophy-

laxis is associated with persistent protection against candidiasis-related

death in allogeneic marrow transplant recipients long-term follow-up of a

randomized placebo-controlled trial Blood 2000 96 2055ndash61

72 AlangadenGChandrasekar PH BaileyE et al Antifungal prophy-

laxis with low-dose fluconazole during bone marrow transplantation The

Bone Marrow Transplantation Team Bone Marrow Transplant 1994 14919ndash24

73 Wolff SN Fay J Stevens D et al Fluconazole versus low-dose

amphotericin B for the prevention of fungal infections in patients under-

going bonemarrow transplantation a study of theNorthAmericanMarrow

Transplant Group Bone Marrow Transplant 2000 25 853ndash9

74 Annaloro C Oriana A Tagliaferri E et al Efficacy of different pro-

phylactic antifungal regimens in bone marrow transplantation Haemato-

logica 1995 80 512ndash17

75 Winston DJ Maziarz RT Chandrasekar PH et al Intravenous and

oral itraconazole versus intravenous and oral fluconazole for long-term

antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant

recipients A multicenter randomized trial Ann Intern Med 2003 138705ndash13

76 MarrKACrippaF LeisenringWet al Itraconazoleversus flucona-

zole forpreventionof fungal infections inpatients receivingallogeneicstem

cell transplants Blood 2004 103 1527ndash33

77 MacMillan ML Goodman JL DeFor TE et al Fluconazole to pre-

vent yeast infections in bone marrow transplantation patients a random-

ized trial of high versus reduced dose and determination of the value of

maintenance therapy Am J Med 2002 112 369ndash79

78 Marr KA Seidel K White TC et al Candidemia in allogeneic blood

and marrow transplant recipients evolution of risk factors after the adop-

tion of prophylactic fluconazole J Infect Dis 2000 181 309ndash16

79 van Burik JA Ratanatharathorn V Stepan DE et al Micafungin

versus fluconazole for prophylaxis against invasive fungal infections dur-

ing neutropenia in patients undergoing hematopoietic stem cell trans-

plantation Clin Infect Dis 2004 39 1407ndash16

80 Prentice HG Kibbler CC Prentice AG Towards a targeted risk-

based antifungal strategy in neutropenic patients Br J Haematol 2000

110 273ndash84

81 Laverdiere M Rotstein C Bow EJ et al Impact of fluconazole

prophylaxis on fungal colonizatin and infection rates in neutropenic

patients The Canadian Fluconazole Study J Animicrob Chemother

2000 46 1001ndash8

82 Winston DJ Chandrasekar PH Lazarus HM et al Fluconazole

prophylaxis of fungal infections in patients with acute leukemia Results

of a randomized placebo-controlled double-blind multicenter trial Ann

Intern Med 1993 118 495ndash503

83 Chandrasekar PHGatnyCMEffect of fluconazole prophylaxis on

fever and use of amphotericin in neutropenic cancer patients Bone Mar-

row Transplantation Team Chemotherapy 1994 40 136ndash43

84 Rotstein C Bow EJ Laverdiere M et al Randomized placebo-

controlled trial of fluconazole prophylaxis for neutropenic cancer patients

benefit basedonpurposeand intensity of cytotoxic therapy TheCanadian

Fluconazole Prophylaxis Study Group Clin Infect Dis 1999 28 331ndash40

85 YamacK Senol E HaznedarR Prophylactic use of fluconazole in

neutropenic cancer patients Postgrad Med J 1997 71 284ndash6

86 KernW BehreG Rudolf T et al Failure of fluconazole prophylaxis

to reducemortality or the requirement of systemic amphotericin B therapy

during treatment for refractory acute myeloid leukemia results of a

Review

406

prospective randomized phase III study German AML Cooperative

Group Cancer 1998 83 291ndash301

87 SchaffnerA SchaffnerM Effect of prophylactic fluconazole on the

frequencyof fungal infectionsamphotericinBuseandhealthcarecosts in

patients undergoing intensive chemotherapy for hematologic neoplasias

J Infect Dis 1995 172 1035ndash41

88 Egger T Gratwohl A Tichelli A et al Comparison of fluconazole

with oral polyenes in the prevention of fungal infections in neutropenic

patients A prospective randomized single-center study Support Care

Cancer 1995 3 139ndash46

89 Morgenstern GR Prentice AG Prentice H et al A randomized

controlled trial of itraconazole versus fluconazole for the prevention of

fungal infections in patients with haematological malignancies UK Mul-

ticentre Antifungal Prophylaxis Study Group Br J Haematol 1999 105901ndash11

90 EllisMEClinkHErnstPetalControlledstudyof fluconazole in the

preventionof fungal infections in neutropenic patientswith haematological

malignancies and bone marrow transplant recipients Eur J Clin Microbiol

Infect Dis 1994 13 3ndash11

91 Philpott-Howard JN Wade JJ Mufti GJ et al Randomized com-

parisonoforal fluconazoleversusoralpolyenes for thepreventionof fungal

infection in patients at risk of neutropenia Multicentre Study Group

J Antimicrob Chemother 1993 31 973ndash84

92 Ninane J A multicentre study of fluconazole versus oral polyenes

in the prevention of fungal infection in children with hematological or

oncological malignancies Multicentre Study Group Eur J Clin Microbiol

Infect Dis 1994 13 330ndash7

93 Menichetti F Del Favero A Martino P et al Preventing fungal

infection in neutropenic patients with acute leukemia fluconazole com-

pared with oral amphotericin B The GIMEMA Infection Program Ann

Intern Med 1994 120 913ndash18

94 Akiyama H Mori S Tanikawa S et al Fluconazole versus oral

amphotericin B in preventing fungal infection in chemotherapy-induced

neutropenic patients with haematological malignancies Mycoses 1996

36 373ndash8

95 Meunier F AounM JanssensM et al Chemoprophylaxis of fungal

infections in granulocytopenic patients using fluconazole versus oral

amphotericin B Drug Invest 1991 3 258ndash65

96 Rozenberg-Arska M Dekker AW Branger J et al A randomized

study to compare oral fluconazole to amphotericin B in the prevention of

fungal infections inpatientswithacute leukaemiaJAntimicrobChemother

1991 27 369ndash76

97 Brammer KW Management of fungal infection in neutropenic

patients with fluconazole Haematol Blood Transfus 1990 33 546ndash50

98 Bodey GP Anaissie EJ Elting LS et al Antifungal prophylaxis

during remission induction therapy for acute leukemia fluconazole versus

intravenous amphotericin B Cancer 1994 73 2099ndash106

99 Kanda Y Yamamoto R Chizuka A et al Prophylactic action of

oral fluconazole against fungal infection in neutropenic patients A

meta-analysis of 16 randomized controlled trials Cancer 2000 891611ndash25

100 Bow EJ Laverdiere M Lussier N et al Antifungal prophylaxis for

severely neutropenic chemotherapy recipients a meta analysis of

randomized-controlled clinical trials Cancer 2002 94 3230ndash46

101 Viscoli C Paesmans M Sanz M et al Association between

antifungal prophylaxis and rate of documented bacteremia in febrile

neutropenic cancer patients Clin Infect Dis 2001 32 1532ndash7

102 HughesWT Armstrong D BodeyGP et al 2002 guidelines for the

use of antimicrobial agents in neutropenic patients with cancerClin Infect

Dis 2002 34 730ndash51

103 Cornely OA Bohme A Buchheidt D et al Prophylaxis of invasive

fungal infections in patients with hematological malignancies and solid

tumorsmdashguidelines of the Infectious Diseases Working Party (AGIHO)

of the German Society of Hematology and Oncology (DGHO) Ann

Hematol 2003 82 Suppl 2 186ndash200

104 McNeil MM Nash SL Hajjeh RA et al Trends in mortality due to

invasivemycotic diseases in theUnitedStates 1980ndash1997Clin InfectDis

2001 33 641ndash7

105 KibblerCCSeatonSBarnesRA et alManagement and outcome

of bloodstream infections due to Candida species in England and Wales

J Hosp Infect 2003 54 18ndash24

106 Marchetti O Bille J Fluckiger U et al Fungal Infection Network of

Switzerland Epidemiology of candidemia in Swiss tertiary care hospitals

secular trends 1991-2000 Clin Infect Dis 2004 38 311ndash20

107 Gudlaugsson O Gillespie S Lee K et al Attributable mortality of

nosocomial candidemia revisited Clin Infect Dis 2003 37 1172ndash7

108 Ibanez-Nolla J Nolla-Salas M Leon MA et al Early diagnosis of

candidiasis in nonneutropenic critically ill patients J Infect 2004 48181ndash92

109 BlumbergHMJarvisWRSoucieJMetalRisk factors for candidal

bloodstream infections in surgical intensive care unit patients the NEMIS

prospective multicenter study The National Epidemiology of Mycosis

Survey Clin Infect Dis 2001 33 177ndash86

110 Pittet D Monod M Suter PM et al Candida colonization and

subsequent infections in critically ill surgical patients Ann Surg 1994

220 751ndash8

111 Sendid B Poirot JL Tabouret M et al Combined detection of

mannanaemia and antimannan antibodies as a strategy for the diagnosis

of systemic infectioncausedbypathogenicCandidaspeciesJMedMicro-

biol 2002 51 433ndash42

112 Bar W Hecker H Diagnosis of systemic Candida infections in

patients of the intensive care unit Significance of serum antigens and

antibodies Mycoses 2002 45 22ndash8

113 Calandra T Marchetti O Clinical trials of antifungal prophy-

laxis among patients undergoing surgery Clin Infect Dis 2004 39S185ndash92

114 Sypula WT Kale-Pradhan PB Therapeutic dilemma of flucona-

zole prophylaxis in intensive care Ann Pharmacother 2002 36 155ndash9

115 Pelz RK Hendrix CW Swoboda SM et al Double-blind placebo-

controlled trial of fluconazole to prevent candidal infections in critically ill

surgical patients Ann Surg 2001 233 542ndash8

116 Eggimann P Francioli P Bille J et al Fluconazole prophylaxis

prevents intraabdominal candidiasis in high-risk surgical patients Crit

Care Med 1997 27 1066ndash72

117 Swoboda SM Merz WG Lipsetta PA Candidemia the impact of

antifungal prophylaxis in a surgical intensive care unitSurg Infect20034345ndash54

118 Todd JC OrsquoNeal VG Grady KP et al Reduction of secondary

mycotic infections in the trauma intensivie care unit with fluconazole

J Trauma 1991 31 1722ndash27

119 Jacobs S Price Evans DA Tariq M et al Fluconazole improves

survival in septic shock a randomized double-blind prospective studyCrit

Care Med 2003 31 1938ndash46

120 Zervos EE Fink GW Norman JG et al Fluconazole increases

bactericidal activity of neutrophils through non-cytokine-mediated path-

way J Trauma 1996 41 465ndash70

121 AblesAZBlumerNAValainisGTetal Fluconazoleprophylaxis of

severe Candida infection in trauma and postsurgical patients a prospec-

tive double-blind randomised placebo-controlled trial Infect Dis Clin

Pract 2000 9 169ndash75

122 Kam LW Lin JD Management of systemic candidal infections in

the intensive care unit Am J Health Syst Pharm 2002 59 33ndash41

123 Rocco TR Reinert SE Simms HH Effects of fluconazole admin-

istration in critically ill patients analysis of bacterial and fungal resistance

Arch Surg 2000 135 160ndash5

124 Tortorano AM Caspani L Rigoni AL et al Candidosis in the inten-

sive care unit a 20-year survey J Hosp Infect 2004 57 8ndash13

125 EggimannPGarbino J Pittet DManagement ofCandida species

infections in critically ill patients Lancet Infect Dis 2003 3 772ndash85

Review

407

126 EggimannPGarbinoJPittetDEpidemiologyofCandida species

infections incritically ill non-immunosuppressedpatientsLancet InfectDis

2003 3 685ndash702

127 Martins MD Lozano-Chiu M Rex JH Declining rates of oropha-

ryngeal candidiasis and carriage of Candida albicans associated with

trends toward reduced rates of carriage of fluconazole-resistant C albi-

cans in human immunodeficiency virus-infected patients Clin Infect Dis

1998 27 1291ndash4

128 Powderly WG Finkelstein D Feinberg J et al A randomized trial

comparing fluconazole with clotrimazole troches for the prevention of fun-

gal infections in patients with advanced human immunodeficiency virus

infection NIAID AIDS Clinical Trials Group N Engl J Med 1995 332700ndash5

129 Leen CL Dunbar EM Ellis ME et al Once-weekly fluconazole to

prevent recurrenceof oropharyngeal candidiasis inpatientswithAIDSand

AIDS-related complex a double-blind placebo-controlled study J Infect

1990 21 55ndash60

130 Stevens DA Greene SI Lang OS Thrush can be prevented in

patients with acquired immunodeficiency syndrome and the acquired

immunodeficiency syndrome-related complex Randomized double-

blind placebo-controlled study of 100-mg oral fluconazole daily Arch

Intern Med 1991 151 2458ndash64

131 Just-Nubling G Gentschew G Meissner K Fluconazole prophy-

laxis of recurrent oral candidiasis inHIV-positive patientsEur JClinMicro-

biol Infect Dis 1991 10 917ndash21

132 Marriott DJ Jones PD Hoy JF et al Fluconazole once a week as

secondary prophylaxis against oropharyngeal candidiasis in HIV-infected

patients A double-blind placebo-controlled studyMed J Aust 1993 158312ndash16

133 Schuman P Capps L Peng G et al Weekly fluconazole for the

prevention ofmucosal candidiasis inwomenwithHIV infection A random-

ized double-blind placebo-controlled trial Terry Beirn Community Pro-

grams for Clinical Research on AIDSAnn InternMed 1997 126 689ndash96

134 Havlir DV DubeMPMcCutchan JA et al Prophylaxis with weekly

versus daily fluconazole for fungal infections in patients with AIDS Clin

Infect Dis 1998 27 1369ndash75

135 Pagani JL Chave JP Casjka C et al Efficacy tolerability and

development of resistance in HIV-positive patients treated with flucona-

zole for secondary prevention of oropharyngeal candidiasis a random-

ized double-blind placebo-controlled trial JAntimicrobChemother 2002

50 231ndash40

136 Vazquez JA Peng G Sobel JD et al Evolution of antifungal sus-

ceptibility amongCandidaspecies isolates recovered fromhuman immun-

odeficiency virus-infected women receiving fluconazole prophylaxis Clin

Infect Dis 2001 33 1069ndash75

137 Delfraissy JF Prise en charge therapeutique des patients infectespas le VIH Rapport Delfraissy Paris Flammarion 2004

138 DePauwBERaemaekers JMDonnelly JPet al Anopenstudyon

the safety and efficacy of fluconazole in the treatment of disseminated

Candida infections in patients treated for hematological malignancy Ann

Hematol 1995 70 83ndash7

139 Anaissie EJ Vartivarian SE Abi-Said D et al Fluconazole versus

amphotericin B in the treatment of hematogenous candidiasis a matched

cohort study Am J Med 1996 101 170ndash6

140 Anaissie EJ Darouiche RO Abi-Said D et al Management of

invasive candidal infections results of a prospective randomized multi-

center study of fluconazole versus amphotericin B and review of the

literature Clin Infect Dis 1996 23 964ndash72

141 Myoken Y Kyo T Kohara T et al Breakthrough fungemia caused

by azole-resistant Candida albicans in neutropenic patients with acute

leukemia Clin Infect Dis 2003 36 1496ndash7

142 Anttila VJ FarkkilaM JanssonSE et al Diagnostic laparoscopy in

patientswith acute leukemiaandsuspectedhepatic candidiasisEur JClin

Microbiol Infect Dis 1997 16 637ndash43

143 Anaissie E Bodey GP Kantarjian H et al Fluconazole therapy for

chronic disseminated candidiasis in patients with leukemia and prior

amphotericin B therapy Am J Med 1991 91 142ndash50

144 KauffmanCA BradleySFRossSC et al Hepatosplenic candidia-

sis successful treatment with fluconazole Am J Med 1991 91 137ndash41

145 Kontoyiannis DP Luna MA Samuels BI et al Hepatosplenic can-

didiasis A manifestation of chronic disseminated candidiasis Infect Dis

Clin North Am 2000 14 721ndash39

146 Graninger W Presteril E Schneeweiss B et al Treatment of

Candida albicans fungaemia with fluconazole J Infect 1993 26 133ndash46

147 Phillips P Shafran S Garber G et al Multicenter randomized trial

of fluconazole versus amphotericin B for treatment of candidemia in

non-neutropenic patients Canadian Candidemia Study Group Eur J

Clin Microbiol Infect Dis 1997 16 337ndash45

148 Rex JH Bennett JE Sugar AM et alA randomized trial comparing

fluconazolewithamphotericinB for the treatmentof candidemia inpatients

without neutropenia Candidemia Study Group and the National Institute

N Engl J Med 1994 331 1325ndash30

149 Abele-Horn M Kopp A Sternberg U et al A randomized study

comparing fluconazolewith amphotericinB5-flucytosine for the treatment

of systemic Candida infections in intensive care patients Infection 1996

24 426ndash32

150 Nguyen MH Peacock JE Jr Tanner DC et al Therapeutic

approaches in patients with candidemia Evaluation in a multicenter

prospective observational study Arch Intern Med 1995 155 2429ndash35

151 Rex JH Pappas PG Karchmer AW et al A randomized and

blinded multicenter trial of high-dose fluconazole plus placebo versus flu-

conazole plus amphotericin B as therapy for candidemia and its con-

sequences in non-neutropenic subjectsClin Infect Dis 2003 36 1221ndash8

152 Mora-Duarte J Betts R Rotstein C et al Comparison of

caspofungin and amphotericin B for invasive candidiasis N Engl J Med

2002 347 2020ndash9

153 Sugar AM Saunders C Diamond RD et al Successful treatment

of Candida osteomyelitis with fluconazole A noncomparative study of

two patients Diagn Microbiol Infect Dis 1990 13 517ndash20

154 Tang C Successful treatment of Candida albicans osteomyelitis

with fluconazole J Infect 1993 26 89ndash92

155 LafontAOliveAGelmanMet alCandidaalbicansspondylodisci-

tis and vertebral osteomyelitis in patients with intravenous heroin drug

addiction Report of 3 new cases J Rheumatol 1994 21 953ndash6

156 Hennequin C Bouree P Hiesse C et al Spondylodiskitis due to

Candida albicans report of two patients who were successfully treated

with fluconazole and review of the literature Clin Infect Dis 1996 23176ndash8

157 Jonnalagadda S VeerabaguMP Rakela J et alCandida albicans

osteomyelitis in a liver transplant recipient a case report and review of the

literature Transplantation 1996 62 1182ndash4

158 Rossel P Schonheyder HC Nielsen H Fluconazole therapy

inCandidaalbicansspondylodiscitisScandJ InfectDis199830 527ndash30

159 TurnerDLJohnsonSARuleSASuccessful treatmentof candidal

osteomyelitis with fluconazole following failure with liposomal ampho-

tericin B J Infect 1999 38 51ndash3

160 El-Zaatari MM Hulten K Fares Y et al Successful treatment of

Candida albicans osteomyelitis of the spine with fluconazole and surgical

debridement case report J Chemother 2002 14 627ndash30

161 Seravalli L Van Linthoudt D Bernet C et al Candida glabrata

spinal osteomyelitis involving two contiguous lumbar vertebrae a case

report and review of the literature Diagn Microbiol Infect Dis 2003 45137ndash41

162 Garbino J Schnyder I LewDP et al An unusual cause of vertebral

osteomyelitis Candida species Scand J Infect Dis 2003 35 288ndash91

163 TunkelARThomasCYWispelweyBCandidaprostheticarthritis

report of a case treated with fluconazole and review of the literature Am J

Med 1993 94 100ndash3

Review

408

164 CushingRD FulgenziWR Synovial fluid levels of fluconazole in a

patient with Candida parapsilosis prosthetic joint infection who had an

excellent clinical response J Arthroplasty 1997 12 950

165 Fukasawa N Shirakura K Candida arthritis after total knee

arthroplastymdasha case of successful treatment without prosthesis removal

Acta Orthop Scand 1997 68 306ndash7

166 Lerch K Kalteis T Schubert T et al Prosthetic joint infections with

osteomyelitis due to Candida albicans Mycoses 2003 46 462ndash6

167 Clancy CJ Nguyen MH Morris AJ Candidal mediastinitis an

emerging clinical entity Clin Infect Dis 1997 25 608ndash13

168 PetrikkosGSkiadaA SabatakouH et al Case report Successful

treatment of two cases of post-surgical sternal osteomyelitis due to

Candida krusei and Candida albicans respectively with high doses of

triazoles (fluconazole itraconazole) Mycoses 2001 44 422ndash5

169 Weers-Pothoff GHavermans JF Kamphuis J et alCandida tropi-

calis arthritis in a patient with acutemyeloid leukemia successfully treated

with fluconazole case report and review of the literature Infection 1997

25 109ndash11

170 Laatikainen L TuominenM vonDickhoff K Treatment of endoge-

nous fungal endophthalmitis with systemic fluconazole with or without

vitrectomy Am J Ophthalmol 1992 113 205ndash7

171 Borne MJ Elliott JH OrsquoDay DM Ocular fluconazole treatment of

Candidaparapsilosisendophthalmitis after failed intravitreal amphotericin

B Arch Ophthalmol 1993 111 1326ndash7

172 Zarbin MA Becker E Witcher J et al Treatment of presumed

fungal endophthalmitis with oral fluconazole Ophthalmic Surg Lasers

1996 27 628ndash31

173 WongVK TasmanWEagleRC et al BilateralCandida parapsilo-

sis endophthalmitis Arch Ophthalmol 1997 115 670ndash2

174 Kauffman CA Bradley SF Vine AK Candida endophthalmitis

associated with intraocular lens implantation efficacy of fluconazole ther-

apy Mycoses 1993 36 13ndash17

175 del Palacio A Cuetara MS Ferro M et al Fluconazole in the man-

agement of endophthalmitis in disseminated candidosis of heroin addicts

Mycoses 1993 36 193ndash9

176 Luttrull JK Wan WL Kubak BM et al Treatment of ocular fungal

infections with oral fluconazole Am J Ophthalmol 1995 119 477ndash81

177 Akler ME Vellend H McNeely DM et al Use of fluconazole in the

treatment of candidal endophthalmitis Clin Infect Dis 1995 20 657ndash64

178 Christmas NJ Smiddy WE Vitrectomy and systemic fluconazole

for treatment of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1996 27 1012ndash18

179 EssmanTFFlynnHWSmiddyWEet al Treatment outcomes in a

10-year study of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1997 28 185ndash94

180 Martinez-Vazquez C Fernandez-Ulloa J Bordon J et al Candida

albicans endophthalmitis in brown heroin addicts response to early vit-

rectomyprecededand followedbyantifungal therapyClin InfectDis1998

27 1130ndash3

181 Aleixo MJ Caldeira L Ferreira ML Candida albicans meningitis

clinical case J Infect 2000 40 191ndash2

182 InoueY YozuR Ueda T et al A case report ofCandida parapsilo-

sis endocarditis J Heart Valve Dis 1998 7 240ndash2

183 Isalska BJ Stanbridge TN Fluconazole in the treatment of candi-

dal prosthetic valve endocarditis BMJ 1988 297 178ndash9

184 Martino P Meloni G Cassone A Candidal endocarditis and treat-

ment with fluconazole and granulocyte-macrophage colony-stimulating

factor Ann Intern Med 1990 112 966ndash7

185 Roupie E Darmon JY Brochard L et al Fluconazole therapy of

candidal native valveendocarditisEur JClinMicrobiol InfectDis199110458ndash9

186 Hernandez JA Gonzalez-Moreno M Llibre JM et al Candidal

mitral endocarditis and long-term treatment with fluconazole in a patient

with human immunodeficiency virus infection Clin Infect Dis 1992 151062ndash3

187 Venditti MDeBernardis FMicozzi A et al Fluconazole treatment

of catheter-related right-sided endocarditis caused by Candida albicans

and associated with endophthalmitis and folliculitis Clin Infect Dis 1992

14 422ndash6

188 Wallbridge DR McCartney AC Richardson MD Fluconazole in

the treatment ofCandidaprosthetic valveendocarditisMycoses199336259ndash61

189 Otaki M Kitamura N Candida prosthetic valve endocarditis An

autopsy review Int Surg 1993 78 252ndash3

190 Czwerwiec FS Bilsker MS Kamerman ML et al Long-term sur-

vival after fluconazole therapy of candidal prosthetic valve endocarditis

Am J Med 1993 94 545ndash6

191 Thakur RK Skelcy KM Kahn RN et al Successful treatment of

Candida prosthetic valve endocarditis with a combination of fluconazole

and amphotericin B Crit Care Med 1994 22 712ndash14

192 Cancelas JA Lopez JCabezudoE et al Native valve endocarditis

due toCandida parapsilosis a late complication after bonemarrow trans-

plantation-related fungemia Bone Marrow Transplant 1994 13 333ndash4

193 Zahid MA Klotz SA Hinthorn DR Medical treatment of recurrent

candidemia in a patient with probable Candida parapsilosis prosthetic

valve endocarditis Chest 1994 105 1597ndash8

194 Wells CJ Leech G Lever AM et al Treatment of native valve

Candida endocarditis with fluconazole J Infect 1995 31 233ndash5

195 Gilbert HM Peters ED Lang SJ et al Successful treatment of

fungal prosthetic valve endocarditis case report and review Clin Infect

Dis 1996 22 348ndash54

196 Nguyen MH Nguyen ML Yu VL et al Candida prosthetic valve

endocarditis prospective study of six cases and review of the literature

Clin Infect Dis 1996 22 262ndash7

197 Lejko-Zupanc T Kozelj M A case of recurrent Candida parapsilo-

sis prosthetic valve endocarditis cure bymedical treatment alone J Infect

1997 35 81ndash2

198 Joly V BelmatougN Leperre A et al Pacemaker endocarditis due

to Candida albicans case report and review Clin Infect Dis 1997 251359ndash62

199 Rex JH Walsh T Sobel JD et al Practice guidelines for the treat-

mentof candidiasis InfectiousDiseasesSocietyofAmericaClin InfectDis

2000 30 662ndash78

200 Baddour LM Long-term suppressive therapy for Candida para-

psilosis-induced prosthetic valve endocarditis Mayo Clin Proc 1995

70 773ndash5

201 Melgar GR Nasser RM Gordon SM Fungal prosthetic valve

endocarditis in 16 patients An 11-year experience in a tertiary care hos-

pital Medicine 1997 76 94ndash103

202 Dupont H Paugam-Burtz C Muller-Serieys C et al Predictive

factors of mortality due to polymicrobial peritonitis with Candida isolation

in peritoneal fluid in critically ill patients Arch Surg 2002 137 1341ndash6

203 Lee SC FungCP ChenHY et alCandida peritonitis due to peptic

ulcer perforation incidence rate risk factors prognosis and susceptibility

to fluconazole and amphotericin B Diagn Microbiol Infect Dis 2002 4423ndash7

204 Levine J Bernard DB Idelson BA et al Fungal peritonitis compli-

cating continuous ambulatory peritoneal dialysis successful treatment

with fluconazole a new orally active antifungal agent Am J Med 1989

86 825ndash7

205 Michel C Courdavault L al Khayat R et al Fungal peritonitis in

patients on peritoneal dialysis Am J Nephrol 1994 14 113ndash20

206 WangAYYuAWLi PKet al Factors predicting outcomeof fungal

peritonitis in peritoneal dialysis analysis of a 9-year experience of fungal

peritonitis in a single center Am J Kidney Dis 2000 36 1183ndash92

207 Hawkins JL Baddour LM Candida lusitaniae infections in the era

of fluconazole availability Clin Infect Dis 2003 36 14ndash18

Review

409

208 KauffmanCAVazquezJASobel JDetal Prospectivemulticenter

surveillance study of funguria in hospitalized patients The National Insti-

tute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group

Clin Infect Dis 2000 30 14ndash18

209 Sobel JD Kauffman CA McKinsey D et al Candiduria a random-

ized double-blind study of treatment with fluconazole and placebo The

National Institute of Allergy and Infectious Diseases (NIAID) Mycoses

Study Group Clin Infect Dis 2000 30 19ndash24

210 LundstromTSobel JNosocomial candiduria a reviewClin Infect

Dis 2001 32 1602ndash7

211 Kaufman D Boyle R Hazen KC et al Fluconazole prophylaxis

against fungal colonization and infection in preterm infants N Engl J

Med 2001 345 1660ndash6

212 Kicklighter SD Springer SC Cox T et al Fluconazole for the pro-

phylaxis against candidal rectal colonization in the very low birth weight

infant Pediatrics 2001 107 293ndash8

213 McGuire W Clerihew L Austin N Prophylactic intravenous anti-

fungal agents to prevent mortality and morbidity in very low birth weight

infants Cochrane Database Syst Rev 2004 CD003850

214 Agarwal JBansalSMalikGKetal Trends inneonatal septicemia

emergence of non-albicans Candida Indian Pediatr 2004 41 712ndash15

215 FasanoCOrsquoKeefe JGibbsD Fluconazole treatment of neonates

and infants with severe fungal infections not treatable with conventional

agents Eur J Clin Microbiol Infect Dis 1994 13 351ndash4

216 Wainer S Cooper PA Gouws H et al Prospective study of flu-

conazole therapy in systemicneonatal fungal infectionPediatr InfectDis J

1997 16 763ndash7

217 Huang YC Lin TY Lien RI et al Fluconazole therapy in neonatal

candidemia Am J Perinatol 2000 17 411ndash15

218 Huttova M Hartmanova I Kralinsky K et al Candida fungemia in

neonates treated with fluconazole report of forty cases including eight

with meningitis Pediatr Infect Dis J 1998 17 1012ndash15

219 Gurpinar AN Balkan E Kilic N et al Fluconazole treatment of

neonates and infants with severe fungal infections J Int Med Res 1997

25 214ndash18

220 Driessen M Ellis JB Muwazi F et al The treatment of systemic

candidiasis in neonates with oral fluconazole Ann Trop Pediatr 1997 17263ndash71

221 Driessen M Ellis JB Cooper PA et al Fluconazole vs

amphotericin B for the treatment of neonatal fungal septicemia

a prospective randomized trial Pediatr Infect Dis J 1997 151107ndash12

222 Marr B Gross S Cunningham C et al Candidal sepsis and

meningitis in a very-low-birth-weight infant successfully treated with flu-

conazole and flucytosine Clin Infect Dis 1994 19 795ndash6

223 Oleinik EM Della-Latta P Rinaldi MG et al Candida lusitaniae

osteomyelitis in a premature infant Am J Perinatol 1993 10 313ndash15

224 Mondal RK Singhi SC Chakrabarti A Randomized comparison

between fluconazole and itraconazole for the treatment of candidemia in a

pediatric intensive care unit a preliminary study Pediatr Crit Care Med

2004 5 561ndash5

225 Viscoli C Castagnola E Fioredda F et al Fluconazole in the treat-

ment of candidiasis in immunocompromised children Antimicrob Agents

Chemother 1991 35 365ndash7

226 Decruyenaere J Colardyn F Vogelaers D et al Combined use of

fluconazole and selective digestive decontamination in the prevention of

fungal infection after adult liver transplantation Transplant Proc 1995 273515ndash16

227 Koh LP Kurup A Goh YT et al Randomized trial of fluconazole

versus low-dose amphotericin B in prophylaxis against fungal infections in

patients undergoing hematopoietic stem cell transplantationAmJHema-

tol 2002 71 260ndash7

228 Gluckman E Esperou-Bourdeau H Ribaud P et al Comparaison

entre le fluconazole et le ketoconazole pour la prophylaxie des infections

fongiques chez les patients traites par greffe de moelle allogenique Cah

Oncol 1993 2 167ndash9

Review

410

fluconazole in that setting with doses ranging from 50 100 or200 mgday to 150 and 400 mgweek129ndash135 Three of themincluded more than 20 patients per arm132133135 (see Table 10)Fluconazole decreased the rate of mucosal infections caused byCandida (vaginal oropharyngeal and oesophageal) Daily regi-mens of fluconazole probably convey better protection againstnew superficial infection events Indeed Havlir et al134 observedsignificantly higher rates of thrush among weekly treated popula-tion than among daily treated (199 versus 123) with shortertime to onset of the initial episode The tolerance of fluconazolewas good Such long-term strategies raise the concern about emer-gence of fluconazole-resistant C albicans and non-albicansstrains

Pagani et al135 identified in vitro fluconazole resistance in12 patients within their cohort of 135 patients Of them eightwere receiving the fluconazole regimen and four were placebo-treated and five presented with clinical failure at the endpoint ofstudy (four receiving fluconazole and one placebo-treated) Theincidence of resistant candidiasis was not found significantly dif-ferent in these two small groups However microbiological resis-tance was significantly associated with the cumulative dose offluconazole before entry in a multiple regression analysis andpatients with clinical failure had received larger cumulativedoses of fluconazole before study entry (mean value 87 g versus29 g) In a similar approach Vazquez et al136 observed that 17of the fluconazole-treated patients had fluconazole-resistant Can-dida sp isolated in the mouth versus only 8 in the placebo groupHowever this difference was not significant

The best prophylaxis for mucosal candidiasis relies on HAARTFor patients with immuno-virological failure fluconazole appearsto be an effective prophylactic drug Noting the probable long-termemergence of resistant strains its use should be limited to thesetting of severe frequent recurrences as suggested in the recentlyupdated French guidelines for HIV care137

Fluconazole in adult neutropenic patients with

systemic candidiasis

Fluconazole is an alternative treatment to amphotericin B in neu-tropenic patients if the infecting strain is susceptible to it Thisconclusion is based on three already dated main studies of whichonly one was randomized and consisted of a small number ofaffected patients138ndash140 De Pauw et al138 showed that fluconazoleat a dose of 400 mgday cured six out of nine patients namely fourof the six patients with candidaemia one of the two patients suf-fering from generalized candidiasis and the fourth patient sufferingfrom Candida-induced meningitis The other two studies showedthat fluconazole at a dose of 400 mgday (in adults) was just aseffective and better tolerated than deoxycholate amphotericin at adose of 06ndash07 mgkgday Fluconazole in neutropenic patients isoften used successfully at higher doses such as 800 mgday (even1200 mgday) but this is not supported by published data Thecombination of fluconazole (800 mgday) and amphotericin B(07 mgkgday) has not been studied in neutropenic patientsThe IDSA is cautious not to recommend the use of fluconazoleas a first line treatment if the patientrsquos condition is not stable andorif the strain has not been identified57 In practice this limits theindication of fluconazole as initial treatment In theory at leastonly patients colonized by a strain that is usually susceptible tofluconazole (C albicans C tropicalis C parapsilosis) and whohave not received azole prophylaxis can be treated by first line

fluconazole141 As long as the yeast is identified as fluconazolesusceptible and the patient is stable fluconazole is indicated inneutropenic patients

Chronic disseminated candidiasis is mostly observed in neu-tropenic patients with haematological malignancies Its incidenceranges from 3 to 7 and is decreasing following the commonpractice of fluconazole as a prophylactic regimen in haematologypatients26142 The efficacy of fluconazole in that setting was evalu-ated only in observational or retrospective studies143144 Anaissieet al143 reported an 88 rate of cure in a series of 20 patients eitherresistant or intolerant to amphotericin B after prescription of flu-conazole (100ndash400 mgday median 30 weeks) Kauffman et al144

similarly reported 100 success in six patients resistant toamphotericin B (200ndash400 mgday for 2ndash14 months) Severalauthors believe that the daily dosage should be raised to 600ndash800 mgday145 In conclusion fluconazole cannot be used asfirst line treatment in the setting of systemic candidiasis amongneutropenic patients It is recommended when switching initialamphotericin B therapy to oral maintenance regimen if the patientwas not previously on fluconazole prophylaxis and was not knownto be colonizedinfected with a less-susceptible or resistant strainTreatment should be maintained for months until disappearance ofcalcification of the lesions especially if further antineoplasticdrugs courses have to be administered

Fluconazole in adult non-neutropenic patients with

candidaemia

Fluconazole has often been used for treatment of fungal infectionsin non-neutropenic patients (see Table 11) Early trials using flu-conazole looked at different doses A paper from the early 1990scompared doses of 5 mgkg versus 10 mgkg to treat candidiasis inICU patients The clinical response rate was better in the 10 mgkggroup and deaths were reduced in this group (24 versus 3) withfluconazole being well tolerated at both doses146 Six studiescompared the efficacy of fluconazole and amphotericin B innon-neutropenic patients with invasive candidiasis139140147ndash150

Of them three were randomized double-blind multicentrestudies140147148 All confirmed the similar efficacy of bothdrugs with better tolerance of the fluconazole regimen In 1994Rex et al148 compared in a randomized prospective multicentrestudy fluconazole (400 mgday) and amphotericin B (05ndash06 mgkgday) among 237 patients Both displayed the same clinical andmicrobiological efficacy and the same mortality rate at 2 weeksIn 1996 Anaissie et al140 performed in the same year a prospec-tive randomized multicentre study of 164 patients (including 104non-neutropenic patients) with more consistency in the fluconazoleand amphotericin B doses (fluconazole 400 mgday amphotericinB 25ndash50 mgday) Although clinical response rates were similarthere was significantly less toxicity in the fluconazole group Phi-lips et al147 in 1997 in a prospective randomized study confirmedthe pattern of efficacy (resolution of fungaemia and death at day14) of fluconazole (400 mgday) and amphotericin B (06 mgkgday) Other kinds of studies were also performed Nguyen et al150

in 1995 failed to find any difference of mortality between thefluconazole-treated (100ndash800 mgday) and amphotericin B-treatedgroups in an open prospective multicentre trial In 1996 Abele-Horn et al149 compared patients hospitalized in ICU treated eitherwith fluconazole (400 mgday on day 1 then 200 mgday) oramphotericin B (1ndash15 mgkgday) plus flucytosine in a random-ized prospective trial no difference in clinicalmicrobiological

Review

397

Table

10

Stu

die

so

nse

con

dar

yp

rop

hy

lact

icfl

uco

naz

ole

amo

ng

HIV

-in

fect

edp

atie

nts

Ref

eren

ceS

tud

yd

esig

nR

egim

en

Du

rati

on

of

trea

tmen

t

Nu

mb

er

of

pat

ien

tsR

ate

of

infe

ctio

ns

Lee

net

al

12

9R

D

B

SC

FL

Cp

o1

50

mg

wee

kv

ersu

sp

lace

bo

24

wee

ks

14

22

10

0

Ste

ven

set

al

13

0R

N

B

SC

FL

Cp

o2

00

mg

day

ver

sus

pla

ceb

o1

2w

eek

s1

20

13

62

Just

-Nu

bli

nget

al

13

1R

N

B

SC

FL

Cp

o5

0m

gd

ayo

r1

00

mg

day

6m

on

ths

18

11

ver

sus

pla

ceb

o1

92

1

21

95

Mar

rio

ttet

al

13

2R

D

B

PC

S

CF

LC

po

15

0m

gw

eek

ver

sus

pla

ceb

o6

mo

nth

s3

54

2

38

96

Sch

um

anet

al

13

3R

D

B

PC

M

CF

LC

20

0m

gw

eek

ver

sus

pla

ceb

o2

9m

on

ths

16

24

4

16

15

8

Hav

liret

al

13

4R

D

B

MC

FL

C4

00

mg

wee

kv

ersu

s2

00

mg

day

52

8d

ays

31

82

0

31

81

2

Pag

aniet

al

13

5R

D

B

PC

S

CF

LC

po

15

0m

gw

eek

ver

sus

pla

ceb

o3

7m

on

ths

67

71

61

71

90

(Plt00001)

Rr

andom

ized

DB

double

bli

ndP

Cp

lace

bo

contr

oll

edS

Cs

ingle

centr

eM

Cm

ult

icen

tre

FL

Cf

luco

naz

ole

poo

ral

OP

Co

rophar

yngea

lcan

did

iasi

sO

Co

eso

ph

agea

lcan

did

iasi

sV

alu

esg

iven

inb

old

face

are

stat

isti

call

ysi

gnif

ican

t

Review

398

Table

11

Stu

die

so

nfl

uco

naz

ole

ascu

rati

ve

trea

tmen

tam

on

gn

on

-neu

tro

pen

icp

atie

nts

Ref

eren

ceS

tud

yd

esig

nK

ind

of

infe

ctio

nR

egim

en

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

tsE

val

uat

ion

item

sE

ffic

acy

Ph

illi

pset

al

14

7R

M

C

PC

can

did

aem

iaF

LC

40

0m

gd

ayiv

ver

sus

AM

B

06

mg

kg

day

iv

4ndash

8w

eek

s5

0

53

clin

ical

mic

robio

logic

al

6m

on

ths

surv

ival

FL

C5

7

AM

B6

2

An

aiss

ieet

al

14

0R

M

C

PC

inv

asiv

e

can

did

iasi

s

FL

C4

00

mg

day

iv

ver

sus

AM

B

25

ndash5

0m

gd

ayiv

9d

ays

75

67

clin

ical

mic

robio

logic

alE

OT

FL

C66

AM

B6

4

An

aiss

ieet

al

13

9O

S

Cca

nd

idae

mia

FL

C2

00

ndash6

00

mg

day

ver

sus

AM

B

03

ndash1

2m

gk

gd

ay

13

day

s

10

day

s

45

45

clin

ical

mic

robio

logic

al

D0

D

5

EO

T

FL

C7

3

AM

B7

1

Ab

ele-

Ho

rnet

al

14

9R

S

Cin

vas

ive

can

did

iasi

s

FL

C2

00

mg

day

iv

ver

sus

AM

B1

ndash1

5m

gk

g

ever

yo

ther

day

+

5F

C3middot

25

gd

ay

14

day

s3

6

36

clin

ical

mic

robio

logic

alE

OT

FL

C64

AM

B+

5F

C6

3

Ng

uy

enet

al

15

0O

M

C

PC

can

did

aem

iaF

LC

10

0ndash

80

0m

gd

ay

ver

sus

AM

B

13

day

s6

7

22

7

dea

thE

OT

no

dif

fere

nce

inm

ort

alit

yat

D+

7D

+1

4

D+

21

Rex

etal

14

8R

D

B

MC

can

did

aem

iaF

LC

40

0m

gd

ayiv

ver

sus

AM

B

06

mg

kg

day

iv

4ndash

8w

eek

s1

03

10

3

clin

ical

mic

robio

logic

alW

12

FL

C70

AM

B7

9

Rr

and

om

ized

D

Bd

ou

ble

bli

nd

S

Bs

ing

leb

lin

dP

Cp

lace

bo

con

tro

lled

S

Cs

ing

lece

ntr

eM

Cm

ult

icen

tre

FL

Cf

luco

naz

ole

A

MB

am

ph

ote

rici

nB

5

FC

flu

cyto

sin

ep

oo

ral

Dd

ayW

wee

kE

OT

en

do

ftr

eatm

ent

iv

intr

aven

ou

s

Review

399

response or death could be found In 1996 Anaissie et al139 com-pared the same drugs in cancer patients with candidiasis andenrolled 90 patients Doses of both fluconazole and amphotericinwere highly variable (fluconazole 200ndash600 mgday amphotericinB 03ndash12 mgkgday) The two cohorts were well matched andresponse rates at day 5 for each cohort were similar overallresponse rates were slightly better for fluconazole and therewere significantly fewer toxic effects in the fluconazole group

A more recent comparison of fluconazole versus fluconazoleplus amphotericin B in non-neutropenic subjects compared 800mgday of fluconazole versus the same dose plus 07 mgkgdayof amphotericin B in a randomized blinded multicentre trial invol-ving 219 patients151 Success rates were slightly higher and therewas a faster clearance rate of candidaemia in the combination groupcompared with fluconazole alone This suggests that the two drugsare not antagonistic and may perhaps act synergistically

Although fluconazole may be the preferred agent in non-neu-tropenic patients because of its low toxicity the recent introductionof caspofungin challenges this place particularly as it has a broaderspectrum of action A randomized study comparing caspofunginversus amphotericin B for the treatment of candidaemia in bothneutropenic and non-neutropenic patients has been completed butthere is no direct comparison with fluconazole152 Results of aprospective randomized controlled multicentre trial comparinganidulafungin a new echinocandin and fluconazole in patientswith candidaemia should be available soon

Fluconazole for the treatment of specific Candida

organ infections

All randomized studies using fluconazole to date have been under-taken in oesophageal candidiasis or candidaemia none in Candidaorgan infection although some patients with invasive candidiasishave been included in the randomized studies Therefore the datapresented here come from non-comparative open-label studies

Osteoarticular infections due to Candida sp

Very few data are available on the efficacy of fluconazole as firstline therapy in osteoarticular infections due to Candida sp Someobservations associated with spondylodiscitis have been publishedand have been summarized in Table 12153ndash162 Fluconazole (200ndash400 mgday initially gt2 months) proved to be efficacious in threecases of knee infections due to C parapsilosis163ndash165 A prostheticjoint infection and osteomyelitis of the knee due toC albicanswerecured with high doses of 800 mgday of fluconazole for 2 months incombination with repeated surgical debridement after a 10 daycourse of fluconazole 400 mgday which seemed to be ineffi-cient166 Fluconazole (400ndash800 mgday for 6 months) was alsoeffective for the treatment ofC albicans post-surgical mediastinitisin two cases167168 Fluconazole (400 mgday for 7 months) suc-cessfully treated an old patient with acute myeloid leukaemia whopresented with C tropicalis arthritis of the knee169 The latestIDSA guidelines recommend surgical debridement and initialcourse of amphotericin B for 2ndash3 weeks followed by fluconazolefor a total duration of 6ndash12 months57

Endophthalmitis due to Candida sp

A combination of partial or complete vitrectomy intraocularamphotericin B and antifungal drugs is the usual therapeuticapproach to Candida sp eye infections Several documented T

able

12

Rep

ort

so

fp

atie

nts

wit

hsp

on

dy

lod

isci

tis

du

eto

Candida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Lo

cali

zati

on

of

infe

ctio

n

Candida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Do

seo

ffl

uco

naz

ole

(mg

day

)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y

(fo

llo

w-u

pd

ura

tio

n)

Gar

bin

oet

al

16

2lu

mb

arCalbicans

14

00

3m

on

ths

(rel

apse

)

then

6m

on

ths

ndashre

cov

ery

(16

mo

nth

s)

lum

bar

Ctropicalis

18

00

foll

ow

edb

yit

raco

naz

ole

reco

ver

y(4

mo

nth

s)

Ser

aval

liet

al

16

1lu

mb

arCglabrata

18

00

3w

eek

sre

pla

ced

by

AM

B(7

0d

ays)

then

lip

idco

mp

lex

(56

day

s)

fail

ure

wit

hfl

uco

naz

ole

then

reco

ver

y(1

6m

on

ths)

El-

Zaa

tariet

al

16

0d

ors

alCalbicans

14

00

3m

on

ths

ndashre

cov

ery

(1y

ear)

Tu

rner

etal

15

9d

ors

o-l

um

bar

Calbicans

12

00

(1m

on

th)

then

10

01

2m

on

ths

afte

rfa

ilu

reo

fA

MB

li

po

som

al

AM

Ban

d5

FC

(9w

eek

s)

reco

ver

y(3

yea

rs)

Ro

ssel

etal

15

8d

ors

alCalbicans

14

00

(14

day

s)th

en2

00

7m

on

ths

afte

rfa

ilu

reo

fA

MB

(21

day

s)re

cov

ery

(1y

ear)

Jon

nal

agad

daet

al

15

7d

ors

alCalbicans

12

00

6m

on

ths

AM

B(3

g)

+5

FC

reco

ver

y(8

mo

nth

s)

Hen

neq

uin

etal

15

6lu

mb

arCalbicans

14

00

6m

on

ths

ndashre

cov

ery

(47

mo

nth

s)

lum

bar

C

alb

ican

s1

20

06

mo

nth

sndash

reco

ver

y(1

7m

on

ths)

Laf

on

tet

al

15

5lu

mb

arCalbicans

14

00

4w

eek

sndash

reco

ver

y(1

8m

on

ths)

Tan

get

al

15

4d

ors

alCalbicans

12

00

1y

ear

ndashre

cov

ery

(16

mo

nth

s)

Su

gar

etal

15

3d

ors

alan

dlu

mb

arCtropicalis

11

00

ndash1

50

1y

ear

AM

B(3

80

mg

)re

cov

ery

(26

mo

nth

s)

AM

B

amphote

rici

nB

5F

C

flucy

tosi

ne

Review

400

clinical cases reported the efficacy of fluconazole alone or incombination with other treatments in cases of endophthalmitisdue to Candida spp16170ndash173 Finally several recent series con-firmed fluconazole efficacy in cases of severe ocular infectionsdue to susceptible Candida sp in non-neutropenic patients174ndash180

Their results are summarized in Table 13 Most cases are due toC albicans and fluconazole-resistant species causing endoph-thalmitis is extremely rare On the basis of these data the IDSArecommends the use of fluconazole in this indication particularlyas follow-up therapy58

Meningitis due to Candida sp

Very few data exist on fluconazolersquos efficacy for the initial treat-ment of Candida sp meningitis in adults although this drug has avery good CSF penetration Oral fluconazole (800 mgday for3 months then 200 mgday) was successful for the treatment ofa C albicans meningitis in an HIV-infected patient with a CD4 cellcount of 35 cellsmm3 who refused intravenous therapy181

Endocarditis due to Candida sp

No series has documented the efficacy of fluconazole in endocard-itis due to Candida sp Only a few clinical cases have been pub-lished and most of these are summarized in Table 14182ndash198 Thesecases illustrate the efficacy of fluconazole (sometimes with nosurgical treatment) in endocarditis due to C albicans and alsoin endocarditis related to some non-albicans Candida spp espe-cially C parapsilosis However no study has demonstrated thesuperiority of fluconazole over amphotericin B in this indicationand there are insufficient data to recommend fluconazole as the firstline treatment for endocarditis due to Candida spp58199 Theechinocandins might have a place as primary therapy in thesecases Fluconazole (200ndash400 mgday) is often employed as partof a long-term suppressive regimen especially if valve replacementis not possible because of the high propensity for delayed relapse ofcandidal endocarditis200201

Peritonitis due to Candida sp

Peritonitis due to Candida sp may develop in patients with peri-toneal dialysis catheters or in those with surgical or traumaticinjury to the gut wall In this latter situation Candida spp areusually part of a polymicrobial infection Isolation of Candidaby direct examination of peritoneal fluid is an independent factorfor a severe outcome202 and recent small studies suggest thatprompt effective adequate and safe antifungal therapy shouldbe given in all cases of Candida sp peritonitis in order to lowerthe mortality rate and shorten the hospital stay113116 In a recentstudy of 23 cases secondary to peptic ulcer perforation the mor-tality rate in patients receiving fluconazole (200 mg intravenouslytwice daily for 2ndash4 weeks) was high (five of eight cases) probablyrelated to inadequate or too late initiation of antifungal therapy203

Some cases showing fluconazole efficacy have been reported inpatients with continuous ambulatory peritoneal dialysis eitheralone or in combination with flucytosine204ndash207 Catheter removalis crucial in these cases

Urinary infections due to Candida spp

Candida is by far the most frequent agent of urinary fungal infec-tions The line between colonization and real infection is generallyblurred Candiduria usually present as nosocomial infections T

able

13

Rep

ort

so

fp

atie

nts

wit

hen

do

ph

thal

mit

isd

ue

toCandida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Met

ho

do

log

y

of

stu

dy

Candida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Do

seo

f

flu

con

azo

le(m

gd

ay)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y

(fo

llo

w-u

pd

ura

tio

n)

Mar

tin

ez-V

azq

uez

etal

18

0p

rosp

ecti

ve

Calbicans

11

40

02

ndash8

wee

ks

AM

Biv

(n=

9)

or

no

trea

tmen

t(n

=1

)u

nti

l

vit

rect

om

y(n

=1

0

2ndash

18

0

day

saf

ter

dia

gn

osi

s)

91

1(6

mo

nth

s)

Ess

man

etal

17

9re

tro

spec

tiv

eCalbicansCtropicalis

5u

nsp

ecif

ied

un

spec

ifie

dv

itre

cto

myndash

loca

lA

MB

55

(25

ndash1

15

mo

nth

s)

Ch

rist

mas

etal

17

8p

rosp

ecti

ve

CalbicansCtropicalis

51

00

ndash2

00

3ndash

6w

eek

sv

itre

cto

my

55

(4ndash

11

mo

nth

s)

Ak

leret

al

17

7re

tro

spec

tiv

eu

nsp

ecif

ied

6to

tal

med

ian

do

se

=9

97

5m

g

med

ian

=5

2d

ays

AM

Biv

lt5

00

mg

+

vit

rect

om

y

1

56

re

lap

se

1(pound

6w

eek

s)

Lu

ttru

llet

al

17

6re

tro

spec

tiv

eCalbicans

(n=

2)

un

spec

ifie

d(n

=2

)

42

00

ndash4

00

4w

eek

s(n

=3

)v

itre

cto

my

1

44

(3ndash

25

mo

nth

sn

=3

)

del

Pal

acio

etal

17

5re

tro

spec

tiv

eCalbicans

74

00

(1d

ay)

then

20

03

wee

ks

ndash6

7(v

itre

cto

my

refu

sal

in

1p

atie

nt)

(Dagger6

mo

nth

s)

Kau

ffm

anet

al

17

4re

tro

spec

tiv

e

len

sim

pla

nts

Cparapsilosis

44

00

(20

0in

pat

ien

ts

wit

hre

nal

fail

ure

)

1y

ear

fail

ure

of

loca

lA

MB

rela

pse

ifn

ole

ns

abla

tio

n

(2y

ears

afte

rst

op

pin

g)

AM

B

amphote

rici

nB

iv

in

trav

enous

Review

401

Table

14

Rep

ort

so

fp

atie

nts

wit

hen

do

card

itis

du

eto

Candida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Val

vu

lar

inv

olv

emen

tCandida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Dose

of

fluco

naz

ole

(mg

day

)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y(f

oll

ow

-up

du

rati

on

)

Ino

ueet

al

18

2ao

rtic

val

ve

Cparapsilosis

16

00

then

40

01

8m

on

ths

surg

ery

reco

ver

y(1

8m

on

ths)

Lej

ko

-Zu

pan

cet

al

19

7m

itra

lp

rost

hes

isCparapsilosis

14

00

(14

day

s)th

en1

00

8m

on

ths

AM

B(3

9g

)A

BC

D

(15

g)

no

rep

lace

men

t

reco

ver

y(gt

3y

ears

)

Joly

etal

19

8p

acem

aker

Calbicans

14

00

(6d

ays)

then

20

07

mo

nth

ssu

rger

yre

cov

ery

(18

mo

nth

s)

Ng

uy

enet

al

19

6ao

rtic

pro

sth

esis

Calbicans

14

00

then

20

04

5y

ears

AM

B+

5F

C

12

wee

ks

no

rep

lace

men

t

reco

ver

y(5

5y

ears

)

Gil

ber

tet

al

19

5ao

rtic

pro

sth

esis

Calbicans

12

00

8m

on

ths

surg

ery

AM

B(2

g)

+

5F

C

40

day

s

reco

ver

y(9

mo

nth

s)

Wel

lset

al

19

4m

itra

lan

dtr

icu

spid

val

ves

Calbicans

12

00

ndash4

00

(14

day

s)

then

40

0th

en5

0

65

mo

nth

s

(40

0m

g)

and

10

mo

nth

s

(50

mg

)

no

rep

lace

men

tre

cov

ery

(45

yea

rs)

Zah

idet

al

19

3m

itra

lv

alv

e

(pro

bab

le)

Cparapsilosis

14

00

18

mo

nth

sA

MB

(5g

)+

5F

C

ket

oco

naz

ole

(80

0m

gd

ay

4m

on

ths)

no

rep

lace

men

t

reco

ver

y(5

yea

rs)

Can

cela

set

al

19

2m

itra

lv

alv

eCparapsilosis

12

00

4m

on

ths

surg

ery

A

MB

(2g

)re

cov

ery

(4m

on

ths)

Th

aku

ret

al

19

1ao

rtic

pro

sth

esis

Calbicans

12

00

6w

eek

sA

MB

(30

mg

day

)

6w

eeks

no

repla

cem

ent

reco

ver

y(2

6m

on

ths)

Czw

erw

iecet

al

19

0ao

rtic

pro

sth

esis

Cparapsilosis

14

00

26

mo

nth

sA

MB

(72

5m

g)

no

rep

lace

men

t

reco

ver

y(2

6m

on

ths)

Ota

kiet

al

18

9m

itra

lp

rost

hes

isCparapsilosis

1u

nsp

ecif

ied

68

day

sn

ore

pla

cem

ent

fail

ure

(dea

thd

ue

toce

reb

ral

hae

mo

rrh

age

and

fev

er)

Wal

lbri

dg

eet

al

18

8m

itra

lp

rost

hes

isCparapsilosis

12

00

-40

0gt

7w

eek

sA

MB

(30

0m

g)

no

rep

lace

men

t

reco

ver

y(6

mo

nth

s)

Ven

dit

tiet

al

18

7in

tera

tria

lse

ptu

mCalbicans

12

00

(28

day

s)th

en6

00

(11

day

s)th

en4

00

6m

on

ths

no

rep

lace

men

tre

cov

ery

(14

mo

nth

s)

Her

nan

dez

etal

18

6m

itra

lv

alv

eCalbicans

12

00

3m

on

ths

AM

Bfa

ilu

ren

o

rep

lace

men

t

imp

rov

emen

t(3

mo

nth

s)

Ro

up

ieet

al

18

5ao

rtic

val

ve

Ctropicalis

14

00

50

day

sn

ore

pla

cem

ent

reco

ver

y(1

1m

on

ths)

Mar

tin

oet

al

18

4in

tera

tria

lse

ptu

mCparapsilosis

13

mg

kg

(7d

ays)

then

6m

gk

g

gt3

mo

nth

sG

M-C

SF

(gt6

wee

ks)

no

rep

lace

men

t

reco

ver

y(5

mo

nth

s)

Isal

skaet

al

18

3m

itra

lp

rost

hes

isCparapsilosis

11

00

ndash2

00

11

mo

nth

sn

ore

pla

cem

ent

reco

ver

y(1

yea

r)

AM

B

amph

ote

rici

nB

5

FC

fl

ucy

tosi

ne

AB

CD

am

ph

ote

rici

nB

coll

oid

ald

isp

ersi

on

G

M-C

SF

g

ran

ulo

cyte

ndashm

on

ocy

teco

lon

y-s

tim

ula

tin

gfa

cto

r

Review

402

favoured by indwelling urinary catheters immunosuppressivedrugs or antibiotic prescriptions diabetes mellitus and extremeages C albicans is involved in half of the cases followed byC glabrata in 15 of the cases In 10 of cases infection involvesmore than one species208 Fluconazole achieves a 10 times higherconcentration in urine than in blood with powerful effect even onCglabrata infections Therefore it represents a first line treatment ofany Candida urinary tract infection

In a randomized placebo-controlled multicentre study amongpatients with asymptomatic candiduria Sobel et al209 found thatfluconazole (200 mgday) hastened the time to negative resultsof urine cultures However the rate of negative urine cultures2 weeks after the end of therapy was similar in the fluconazole-and placebo-treated groups showing the minimal utility of treat-ment in that setting Indeed asymptomatic candiduria should betreated only in high-risk situations namely patients with neutrope-nia infants with low birth weight patients with renal allografts andpatients who will undergo urologic manipulations (recommenda-tion of grade B-III from the IDSA) The optimal regimen in thatsetting is not known Short courses regimen are not recommendedand therapy for 1ndash2 weeks should be efficient

Ascending pyelonephritis treatment should also include ade-quate urinary drainage and removal of obstructive fungusballs210 Urinary tract devices should be optimally removed orat least replaced

Haematogenous renal involvement should be treated with high-dose parenteral fluconazole (6 mgkgday) in accordance with therecently published IDSA guidelines57

Fluconazole in childreninfants

No specific approval of fluconazole has been obtained inyoung children before the age of 6 months but a few studieshave evaluated its use in several settings

Prophylaxis of systemic candidiasis in neonates

Few studies have focused on the use of fluconazole as a prophy-lactic agent against invasive candidiasis in neonates Kaufmanet al211 demonstrated in 2001 the efficacy and safety of flucona-zole (3 mgkg every 3 days during the first 2 weeks then every2 days during the following 2 weeks and then every day until thesixth week of life) in extremely low birth weight and high-riskinfants (lt1000 g) in preventing both colonization and invasivefungal infection High risk was defined as the presence of a centralvascular catheter or endotracheal tube Indeed among the 50infants randomly assigned to fluconazole the rate of colonization(22) was significantly lower than in the 50 placebo-treated ones(60) no invasive fungal infection developed in the fluconazolegroup compared with a 20 rate of infection in the placebo groupNo adverse effect of fluconazole was documented

Kicklighter et al212 similarly observed the safety of fluconazoleat 6 mgkg (for 6 weeks) and its efficacy among neonates with lowbirth weight (lt1500 g) in the prevention of rectal colonization(however occurrence of invasive candidiasis was similar inboth groups) A Cochrane review of fluconazole prophylaxis inpreterm infants demonstrated a reduced risk of invasive infection(related risk 020) and mortality (related risk 044) in fluconazole-treated patients compared with placebo-treated patients213

Although concerns about resistance to azoles have been raised

the vast majority ofCandida spp strains have remained susceptibleto fluconazole over the past decade in this population40

Fluconazole in systemic candidiasis in childreninfants

Neonatal candidaemia Candidaemia is a major cause of sepsis inneonatal ICU representing up to 16 of all sepsis cases Therelated mortality rate is high often nearly 50214 Most casesare related to C albicans and C parapsilosis with a recent risein cases related to C tropicalis The main risk factors for invasivecandidiasis among neonates are low birth weight intravascularcatheters intratracheal intubation total parenteral nutrition andadministration of intralipid solution and recent administration ofbroad-spectrum antibiotics and corticosteroids10

Treatment with amphotericin B and 5-flucytosine has been thegold standard for years However amphotericin B has some seriousside effects which makes it mandatory to consider its use in thatsetting With good profile of tolerance good diffusion in all tissuesand body fluids and reliable oral absorption fluconazole has beenstudied as an alternative (see Table 15) In 1994 Fasano et al215

reported the compassionate use of fluconazole among 40 new-borns including 11 who presented with Candida sp meningitisThey were treated with a mean daily dosage of 5 mgkgday for amean duration of 26 days Of the 32 patients with evaluable out-come 31 experienced clearance of infection Other studies haveconfirmed these results in the recent years11216ndash220 In a multicen-tre prospective randomized study Driessen et al220 compared theefficacy and safety of either amphotericin B ndash 5-flucytosine orfluconazole (oral or intravenous dose of 10 mgkg as initialdose and then 5 mgkgday) in neonates with candidaemia Inthe fluconazole group 812 (67) survived versus 611 (55) inthe other group220 Among the four patients who died in the flu-conazole group two had treatment failure versus one in the ampho-tericin B group Cytolytic hepatitis was less frequent in thefluconazole-treated group Two isolated case reports also suggestthat the association of fluconazole and flucytosine might be syn-ergistic in the treatment of neonatal candidaemia222223

Very recently Mondal et al229 compared the efficacy and safetyof oral itraconazole versus oral fluconazole (both doses of 10 mgkgday) in newborns and paediatric patients with candidaemiaSimilar cure rate (81 and 82) mortality rate (95 and 135)and number of side effects were observed224 Fluconazole thusappears as a safe and effective systemic antifungal agent in thesetting of neonatal candidiasis

Children with systemic candidiasis Excluding the setting of neo-natal candidiasis very few studies have however focused on thepaediatric population when studying the efficiency of fluconazolefor the treatment of invasive candidiasis

In 1991 Viscoli et al reported the outcome of 24 immunocom-promised children treated with fluconazole (6 mgkgday) for 34episodes of proven invasive candidiasis A total of 3034 clinicaland microbiological cures were achieved Two patients with fun-gaemia due toC parapsilosis required an increase in dosage of up to12 mgkg Transient drug-related increases of liver transaminasesoccurred in two cases (6)225 In 1994 Fasano et al reported theoutcome of 63 children with AIDS cancer or transplantationprospectively receiving fluconazole as compassionate treatment(dose regimen ranging from 016 to 11 mgkgday mean 34 mgkgday)215 Half of them had fungaemia while the others hadrespiratory urinary tract or superficial oropharyngeal infections

Review

403

Clinical cure or improvement was achieved in 5263 (83) andpathogen eradication was achieved in 4359 (73)17 Huttovaet al218 reported in 1998 the outcome of 10 children withnosocomial fungal meningitis including 8 cases of candidal men-ingitis treated using fluconazole Five of them survived with clinicaland microbiological cure

Conclusions

Almost 15 years after its launch fluconazole remains a cornerstoneof antifungal prophylaxis and therapy of invasive candidiasis It hasan excellent pharmacokinetic and safety profile even in debilitatedpatients with good tissue penetration and a lack of major druginteractions particularly with immunosuppressive agents It can beprescribed in patients with renal failure if daily dosages are adaptedto the creatinine serum level Its spectrum of antimicrobial efficacyis reasonable and it remains active against most intrinsically sus-ceptible Candida spp encountered in systemic disease with lt5of C albicans resistant to fluconazole in that setting Although Ckrusei is intrinsically resistant to fluconazole it is rarely reported asa cause of systemic infection outside neutropenic patients Thus Cglabrata is the only species which might now limit the use offluconazole for the first line therapy of yeast fungaemia whenthe species is not identified Similarly patients who recentlyreceived fluconazole as antifungal prophylaxis should not be trea-ted with fluconazole for the curative treatment of a presumed orproven episode of systemic candidiasis The fungistatic effect offluconazole against Candida spp does not appear to influence theoutcome of candidaemic episodes at least in comparison withamphotericin B which is apparently fungicidal against Candidaspp Finally when summarizing its valuable properties the strongdemonstration of its efficacy in large randomized controlled trialsand selected clinical series its availability in various commercialpresentations and its current low cost fluconazole still remains aleading antifungal drug against susceptible Candida species

Transparency declarations

C C E H A L P R and F D have no conflicts to declareD W D In the past 5 years D W D has received grant supportfrom Astellas Merck Pfizer F2G OrthoBiotech Indevus Basileathe Fungal Research Trust the Wellcome Trust the National Insti-tute of Allergy and Infectious Diseases and the European Union Hehas been an advisorconsultant to Merck Basilea Vicuron (nowPfizer) Schering Plough Indevus F2G Nektar Daiichi SigmaTau Astellas PPL Therapeutics and Uriach He has been paid fortalks on behalf of Astellas Merck and Pfizer He holds foundershares in F2G Ltd and GBE Diagnostics Ltd and talks on behalf ofAstellas Merck and Gilead Sciences O L Speakers bureau forPfizer

References

1 Richardson K The discovery and profile of fluconazole J Chemo-

ther 1990 2 51ndash4

2 Richardson K Brammer KW Marriott MS et al Activity of

UK-49858 a bis-triazole derivative against experimental infections

with Candida albicans and Trichophyton mentagrophytes Antimicrob

Agents Chemother 1985 27 832ndash5

3 Vanrsquot Wout JW Mattie H van Furth R A prospective study of the

efficacyof fluconazole (UK-49858)againstdeep-seated fungal infections

J Antimicrob Chemother 1988 21 665ndash72Table

15

No

n-c

om

par

ativ

est

ud

ies

on

flu

con

azo

leas

cura

tiv

etr

eatm

ent

of

neo

nat

alca

nd

idae

mia

Ref

eren

ce

Nu

mb

ero

f

pat

ien

tsR

egim

enM

icro

bio

log

ical

cure

Sid

eef

fect

s

Dri

esse

net

al

22

02

1v

ery

low

bir

thw

eig

ht

5m

gk

gfo

r

1ndash

42

day

sm

ean

16

90

3

0

cyto

lyti

ch

epat

itis

Fas

anoet

al

21

54

05

mg

kg

for

2ndash

80

day

sm

ean

26

97

5

cy

toly

tic

hep

atit

is

Wai

ner

etal

21

61

91

0m

gk

go

nd

ay1

then

5m

gk

g

63

su

rviv

ing

32

fun

gal

free

dea

ths

NS

Hu

anget

al

21

71

8v

ery

low

bir

thw

eig

ht

3ndash

10

mg

kg

for

15

ndash1

73

day

sm

ean

34

6fi

rst

lin

etr

eatm

ent

83

13

afte

rA

MB

fail

ure

6

2

29

cy

toly

tic

hep

atit

is

Hu

tto

vaet

al

21

84

0v

ery

low

bir

thw

eig

ht

6m

gk

gfo

r6

ndash4

8d

ays

65

cu

rew

ith

ou

tre

lap

se5

cy

toly

tic

hep

atit

is

5

-ele

vat

edse

rum

crea

tin

ine

Gu

rpin

aret

al

21

92

42

ndash1

6m

gk

gfo

r

5ndash

72

day

sm

ean

25

96

8

an

aem

iao

rcy

toly

tic

hep

atit

is

Sch

war

zeet

al

11

53

5ndash

6m

gk

gfo

r3

wee

ks

mea

n2

17

8

4

cyto

lyti

ch

epat

itis

AM

B

amphote

rici

nB

ver

ylo

wbir

thw

eight

lt1500

g

NS

st

atis

tica

lly

not

signif

ican

t

Review

404

4 Vanrsquot Wout JW deGraeff-Meeder ER Paul LC et al Treatment of

two cases of cryptococcal meningitis with fluconazole Scand J Infect Dis

1988 20 193ndash8

5 Tucker RM Williams PL Arathoon EG et al Pharmacokinetics of

fluconazole in cerebrospinal fluid and serum in human coccidioidal

meningitis Antimicrob Agents Chemother 1988 32 369ndash73

6 ByrneWRWajszczukCPCryptococcalmeningitis in theacquired

immunodeficiency syndrome (AIDS) successful treatment with flucona-

zole after failure of amphotericin B Ann Intern Med 1988 108 384ndash5

7 HughesCE BeggsWH Action of fluconazole (UK-49858) in rela-

tion to other systemic antifungal azoles J Antimicrob Chemother 1987

19 171ndash4

8 DebruyneDClinicalpharmacokineticsof fluconazole insuperficial

and systemic mycoses Clin Pharmacokinet 1997 33 52ndash77

9 Brammer KW Coates PE Pharmacokinetics of fluconazole in

pediatric patients Eur J Clin Microbiol Infect Dis 1994 13 325ndash9

10 Schwarze R Penk A Pittrow L Administration of fluconazole in

children below 1 year of age Mycoses 1999 42 3ndash16

11 Schwarze R Penk A Pittrow L Treatment of candidal infections

with fluconazole in neonates and infants Eur J Med Res 2000 5 203ndash8

12 Thaler FBernardBTodMet al Fluconazolepenetration in cereb-

ral parenchyma in humans at steady stateAntimicrob Agents Chemother

1995 5 1154ndash6

13 Bozzette SA Gordon RL Yen A et al Biliary concentrations of

fluconazole in a patient with candidal cholecystitis case reportClin Infect

Dis 1992 4 701ndash3

14 Debruyne D Ryckelynck JP Moulin M et al Pharmacokinetics of

fluconazole in patients undergoing continuous ambulatory peritoneal dial-

ysis Clin Pharmacokinet 1990 18 491ndash8

15 Tod M Lortholary O Padoin C et al Intravenous penetration of

fluconazole during endophthalmitis Clin Microbiol Infect 1997 3 143ndash4

16 Urbak SF Degn T Fluconazole in the management of fungal ocu-

lar infections Ophthalmologica 1994 3 147ndash56

17 Fasano C OrsquoKeefe J Gibbs D Fluconazole treatment of children

with severe fungal infections not treatable with conventional agentsEur J

Clin Microbiol Infect Dis 1994 13 344ndash7

18 Aleck KA Bartley DL Multiple malformation syndrome following

fluconazole use in pregnancy report of an additional patient Am J Med

Genet 1997 72 253ndash6

19 Buijk SL Gyssens IC Mouton JW et al Pharmacokinetics of

sequential intravenous and enteral fluconazole in critically ill surgical

patients with invasive mycoses and compromised gastro-intestinal func-

tion Intensive Care Med 2001 27 115ndash21

20 El-Yazigi AEllisMErnstPet al Pharmacokinetics of oral flucona-

zole when used for prophylaxis in bone marrow transplant recipients

Antimicrob Agents Chemother 1997 41 914ndash17

21 Finch CK Green CA Self TH Fluconazole-carbamazepine inter-

action South Med J 2002 95 1099ndash100

22 Tucker RM Denning DW Hanson RH et al Interaction of azoles

with rifampin phenytoin and carbamazepine in vitro and clinical obser-

vations Clin Infect Dis 1992 14 165ndash74

23 Stockley IH Stockleyrsquos Drug Interactions A Source Book of Inter-

actions Their Mechanisms Clinical Importance and Management 6th

edn London UK Pharmaceutical Press 2002

24 von Moltke LL Greenblatt DJ Duan SX et al Inhibition of terfena-

dine metabolism in vitro by azole antifungal agents and by selective sero-

tonin reuptake inhibitor antidepressants relation to pharmacokinetic

interactions in vivo J Clin Psychopharmacol 1996 16 104ndash12

25 BrockmeyerNH Tillmann I Mertins L et al Pharmacokinetic inter-

action of fluconazole and zidovudine in HIV-positive patients Eur J Med

Res 1997 2 377ndash83

26 van Burik JA LeisenringW Myerson D et al The effect of prophy-

lactic fluconazole on the clinical spectrum of fungal diseases in bone

marrow transplant recipients with special attention to hepatic candidiasis

An autopsy study of 355 patients Medicine 1998 77 246ndash54

27 Wingard JR Antifungal chemoprophylaxis after blood andmarrow

transplantation Clin Infect Dis 2002 34 1386ndash90

28 GarbinoJLewDPRomandJAetalPreventionofsevereCandida

infections in nonneutropenic high-risk critically ill patients a randomized

double-blind placebo-controlled trial in patients treatedbyselectivediges-

tive decontamination Intensive Care Med 2002 28 1708ndash17

29 Gearhart MO Worsening of liver function with fluconazole and

review of azole antifungal hepatotoxicity Ann Pharmacother 1994 281177ndash81

30 Crerar-Gilbert A Boots R Fraenkel D et al Survival following ful-

minant hepatic failure from fluconazole induced hepatitis Anaesth Inten-

sive Care 1999 27 650ndash2

31 PappasPGKauffmanCAPerfect Jetal Alopeciaassociatedwith

fluconazole therapy Ann Intern Med 1995 123 354ndash7

32 Stevens DA Diaz M Negroni R et al Safety evaluation of chronic

fluconazole therapy Fluconazole Pan-American Study Group

Chemotherapy 1997 5 371ndash7

33 Anaissie EJ Kontoyiannis DP Huls C et al Safety plasma con-

centrations and efficacy of high-dose fluconazole in invasive mold infec-

tions J Infect Dis 1995 172 599ndash602

34 Gussenhoven MJ Haak A Peereboom-Wynia JD et al Stevens-

Johnson syndrome after fluconazole Lancet 1991 338 120

35 NovelliVHolzelHSafetyand tolerabilityof fluconazole inchildrenAntimicrob Agents Chemother 1999 43 1955ndash60

36 Koks CH Crommentuyn KM Hoetelmans RM et al Can

fluconazole concentrations in saliva be used for therapeutic drug mon-

itoring Ther Drug Monit 2001 4 449ndash53

37 Louie A Drusano GL Banerjee P et al Pharmacodynamics of

fluconazole in amurinemodel of systemic candidiasisAntimicrob Agents

Chemother 1998 42 1105ndash9

38 PittrowLPenkAPlasmaand tissueconcentrationsof fluconazole

and their correlation to breakpoints Mycoses 1997 40 25ndash32

39 Rex JH Pfaller MA Galgiani JN et al Development of interpretive

breakpoints forantifungalsusceptibility testing conceptual frameworkand

analysis of in vitro-in vivo correlation data for fluconazole itraconazole

and Candida infections Subcommittee on Antifungal Susceptibility Test-

ingof theNationalCommittee forClinical LaboratoryStandardsClin Infect

Dis 1997 24 235ndash47

40 Pfaller MA Diekema DJ Twelve years of fluconazole in clinical

practiceglobal trends inspeciesdistributionand fluconazolesusceptibility

of bloodstream isolatesofCandida International FungalSurveillancePar-

ticipant Group Clin Microbiol Infect 2004 10 Suppl 1 11ndash23

41 Tortorano AM Rigoni AL Biraghi E et al The European Confed-

eration of Medical Mycology (ECMM) survey of candidaemia in Italy anti-

fungal susceptibility patterns of 261 non-albicans Candida isolates from

blood J Antimicrob Chemother 2003 52 679ndash82

42 Pfaller MAMesser SA Boyken L et al Geographic variation in the

susceptibilities of invasive isolates of Candida glabrata to seven systemi-

cally active antifungal agents a global assessment from the ARTEMIS

Antifungal Surveillance Program conducted in 2001 and 2002 J Clin

Microbiol 2004 42 3142ndash6

43 Paya CV Fungal infections in solid-organ transplantation Clin

Infect Dis 1993 16 677ndash88

44 Singh N Wagener MM Marino IR et al Trends in invasive fungal

infections in liver transplant recipients correlation with evolution in trans-

plantation practices Transplantation 2002 73 63ndash7

45 Fung JJ Fungal infection in liver transplantation Transplant InfectDis 2002 4 18ndash23

46 Winston DJ Pakrasi A Busuttil RW Prophylactic fluconazole in

liver transplant recipientsA randomized double-blind placebo-controlled

trial Ann Intern Med 1999 131 729ndash37

47 Gladdy RA Richardson SE Davies HD et al Candida infection in

pediatric liver transplant recipients Liver Transpl Surg 1999 5 16ndash24

Review

405

48 Castaldo P Stratta RJ Wood RP et al Clinical spectrum of fungal

infections after orthotopic liver transplantation Arch Surg 1991 126149ndash56

49 Husain S Tollemar J Dominguez EA et al Changes in the spec-

trum and risk factors for invasive candidiasis in liver transplant recipients

prospective multicenter case-controlled study Transplantation 2003

75 2023ndash9

50 GeorgeMJ Snydman DRWerner BG et al The independent role

of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic

liver transplant recipients Boston Center for Liver Transplantation

CMVIG-Study Group Cytogam MedImmune Inc Gaithersburg Mary-

land Am J Med 1997 103 106ndash13

51 Dockrell DH Mendez JC Jones M et al Human herpesvirus 6

seronegativity before transplantation predicts the occurrence of fungal

infection in liver transplant recipientsTransplantation 1999 67 399ndash403

52 Tollemar J Ericzon BG Barkholt L et al Risk factors for deep

Candida infections in liver transplant recipients Transplant Proc 1990

22 1826ndash7

53 Lumbreras C Cuervas-Mons V Jara P et al Randomized trial of

fluconazole versus nystatin for the prophylaxis of Candida infection

following liver transplantation J Infect Dis 1996 174 583ndash8

54 Winston DJ Busuttil RW Randomized controlled trial of oral itra-

conazole solution versus intravenousoral fluconazole for prevention of

fungal infections in liver transplant recipients Transplantation 2002

74 688ndash95

55 Tortorano AM Viviani MA PaganoA et al Candida colonization in

orthotopic liver tranplantation fuconazole versus oral amphoericin B

J Mycol Med 1995 5 21ndash4

56 Kung N Fisher N Gunson B et al Fluconazole prophylaxis for

high-risk liver transplant recipients Lancet 1995 345 1234ndash5

57 Pappas PG Rex JH Sobel JD et al Guidelines for treatment of

candidiasis Clin Infect Dis 2004 38 161ndash89

58 PayaCV Prevention of fungal infection in transplantation TransplInfect Dis 2002 4 S46ndash51

59 LortholaryO Dupont B Antifungal prophylaxis during neutropenia

and immunodeficiency Clin Microbiol Rev 1997 10 477ndash504

60 Benedetti E Gruessner AC Troppmann C et al Intra-abdominal

fungal infections after pancreatic transplantation incidence treatment

and outcome J Am Coll Surg 1996 183 307ndash16

61 LumbrerasC Fernandez I Velosa J et al Infectious complications

following pancreatic transplantation incidence microbiological and clini-

cal characteristics and outcome Clin Infect Dis 1995 20 514ndash20

62 Patterson JE Epidemiology of fungal infections in solid organ

transplant patients Transpl Infect Dis 1999 1 229ndash36

63 Kusne S Furukawa H Abu-Elmagd K et al Infectious complica-

tions after small bowel transplantation in adults an update Transplant

Proc 1996 28 2761ndash2

64 Paterson DL Ndirangu M Kwak EJ et al Opportunistic infections

in solid-organ transplant recipients pre-treated with alumetuzumab In

Abstracts of the Forty-Fourth Interscience Conference on Antimicrobial

Agents and Chemotherapy Washington DC 2004 Abstract K-1427 p

357 American Society for Microbiology Washington DC USA

65 Kramer MR Marshall SE Starnes VA et al Infectious complica-

tions in heart-lung transplantation Analysis of 200 episodes Arch Intern

Med 1993 153 2010ndash6

66 Goodrich JMReedECMori M et al Clinical features and analysis

of risk factors for invasive candidal infection after marrow transplantation

J Infect Dis 1991 164 731ndash40

67 Dykewicz CA Centers for Disease Control and Prevention (US)

Infectious Diseases Society of America American Society of Blood and

MarrowTransplantation Summary of the guidelines for preventing oppor-

tunistic infections among hematopoietic stem cell transplant recipients

Clin Infect Dis 2001 33 139ndash44

68 Sable CA Donowitz GR Infections in bone marrow transplant

recipients Clin Infect Dis 1994 18 273ndash81

69 Goodman JLWinston DJ Greenfield RA et al A controlled trial of

fluconazole to prevent fungal infections in patients undergoing bone mar-

row transplantation N Engl J Med 1992 326 845ndash51

70 Slavin MA Osborne B Adams R et al Efficacy and safety of flu-

conazole prophylaxis for fungal infectionsaftermarrow transplantationmdasha

prospective randomized double-blind study J Infect Dis 1995 1711545ndash52

71 Marr KA Seidel K SlavinMA et al Prolonged fluconazole prophy-

laxis is associated with persistent protection against candidiasis-related

death in allogeneic marrow transplant recipients long-term follow-up of a

randomized placebo-controlled trial Blood 2000 96 2055ndash61

72 AlangadenGChandrasekar PH BaileyE et al Antifungal prophy-

laxis with low-dose fluconazole during bone marrow transplantation The

Bone Marrow Transplantation Team Bone Marrow Transplant 1994 14919ndash24

73 Wolff SN Fay J Stevens D et al Fluconazole versus low-dose

amphotericin B for the prevention of fungal infections in patients under-

going bonemarrow transplantation a study of theNorthAmericanMarrow

Transplant Group Bone Marrow Transplant 2000 25 853ndash9

74 Annaloro C Oriana A Tagliaferri E et al Efficacy of different pro-

phylactic antifungal regimens in bone marrow transplantation Haemato-

logica 1995 80 512ndash17

75 Winston DJ Maziarz RT Chandrasekar PH et al Intravenous and

oral itraconazole versus intravenous and oral fluconazole for long-term

antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant

recipients A multicenter randomized trial Ann Intern Med 2003 138705ndash13

76 MarrKACrippaF LeisenringWet al Itraconazoleversus flucona-

zole forpreventionof fungal infections inpatients receivingallogeneicstem

cell transplants Blood 2004 103 1527ndash33

77 MacMillan ML Goodman JL DeFor TE et al Fluconazole to pre-

vent yeast infections in bone marrow transplantation patients a random-

ized trial of high versus reduced dose and determination of the value of

maintenance therapy Am J Med 2002 112 369ndash79

78 Marr KA Seidel K White TC et al Candidemia in allogeneic blood

and marrow transplant recipients evolution of risk factors after the adop-

tion of prophylactic fluconazole J Infect Dis 2000 181 309ndash16

79 van Burik JA Ratanatharathorn V Stepan DE et al Micafungin

versus fluconazole for prophylaxis against invasive fungal infections dur-

ing neutropenia in patients undergoing hematopoietic stem cell trans-

plantation Clin Infect Dis 2004 39 1407ndash16

80 Prentice HG Kibbler CC Prentice AG Towards a targeted risk-

based antifungal strategy in neutropenic patients Br J Haematol 2000

110 273ndash84

81 Laverdiere M Rotstein C Bow EJ et al Impact of fluconazole

prophylaxis on fungal colonizatin and infection rates in neutropenic

patients The Canadian Fluconazole Study J Animicrob Chemother

2000 46 1001ndash8

82 Winston DJ Chandrasekar PH Lazarus HM et al Fluconazole

prophylaxis of fungal infections in patients with acute leukemia Results

of a randomized placebo-controlled double-blind multicenter trial Ann

Intern Med 1993 118 495ndash503

83 Chandrasekar PHGatnyCMEffect of fluconazole prophylaxis on

fever and use of amphotericin in neutropenic cancer patients Bone Mar-

row Transplantation Team Chemotherapy 1994 40 136ndash43

84 Rotstein C Bow EJ Laverdiere M et al Randomized placebo-

controlled trial of fluconazole prophylaxis for neutropenic cancer patients

benefit basedonpurposeand intensity of cytotoxic therapy TheCanadian

Fluconazole Prophylaxis Study Group Clin Infect Dis 1999 28 331ndash40

85 YamacK Senol E HaznedarR Prophylactic use of fluconazole in

neutropenic cancer patients Postgrad Med J 1997 71 284ndash6

86 KernW BehreG Rudolf T et al Failure of fluconazole prophylaxis

to reducemortality or the requirement of systemic amphotericin B therapy

during treatment for refractory acute myeloid leukemia results of a

Review

406

prospective randomized phase III study German AML Cooperative

Group Cancer 1998 83 291ndash301

87 SchaffnerA SchaffnerM Effect of prophylactic fluconazole on the

frequencyof fungal infectionsamphotericinBuseandhealthcarecosts in

patients undergoing intensive chemotherapy for hematologic neoplasias

J Infect Dis 1995 172 1035ndash41

88 Egger T Gratwohl A Tichelli A et al Comparison of fluconazole

with oral polyenes in the prevention of fungal infections in neutropenic

patients A prospective randomized single-center study Support Care

Cancer 1995 3 139ndash46

89 Morgenstern GR Prentice AG Prentice H et al A randomized

controlled trial of itraconazole versus fluconazole for the prevention of

fungal infections in patients with haematological malignancies UK Mul-

ticentre Antifungal Prophylaxis Study Group Br J Haematol 1999 105901ndash11

90 EllisMEClinkHErnstPetalControlledstudyof fluconazole in the

preventionof fungal infections in neutropenic patientswith haematological

malignancies and bone marrow transplant recipients Eur J Clin Microbiol

Infect Dis 1994 13 3ndash11

91 Philpott-Howard JN Wade JJ Mufti GJ et al Randomized com-

parisonoforal fluconazoleversusoralpolyenes for thepreventionof fungal

infection in patients at risk of neutropenia Multicentre Study Group

J Antimicrob Chemother 1993 31 973ndash84

92 Ninane J A multicentre study of fluconazole versus oral polyenes

in the prevention of fungal infection in children with hematological or

oncological malignancies Multicentre Study Group Eur J Clin Microbiol

Infect Dis 1994 13 330ndash7

93 Menichetti F Del Favero A Martino P et al Preventing fungal

infection in neutropenic patients with acute leukemia fluconazole com-

pared with oral amphotericin B The GIMEMA Infection Program Ann

Intern Med 1994 120 913ndash18

94 Akiyama H Mori S Tanikawa S et al Fluconazole versus oral

amphotericin B in preventing fungal infection in chemotherapy-induced

neutropenic patients with haematological malignancies Mycoses 1996

36 373ndash8

95 Meunier F AounM JanssensM et al Chemoprophylaxis of fungal

infections in granulocytopenic patients using fluconazole versus oral

amphotericin B Drug Invest 1991 3 258ndash65

96 Rozenberg-Arska M Dekker AW Branger J et al A randomized

study to compare oral fluconazole to amphotericin B in the prevention of

fungal infections inpatientswithacute leukaemiaJAntimicrobChemother

1991 27 369ndash76

97 Brammer KW Management of fungal infection in neutropenic

patients with fluconazole Haematol Blood Transfus 1990 33 546ndash50

98 Bodey GP Anaissie EJ Elting LS et al Antifungal prophylaxis

during remission induction therapy for acute leukemia fluconazole versus

intravenous amphotericin B Cancer 1994 73 2099ndash106

99 Kanda Y Yamamoto R Chizuka A et al Prophylactic action of

oral fluconazole against fungal infection in neutropenic patients A

meta-analysis of 16 randomized controlled trials Cancer 2000 891611ndash25

100 Bow EJ Laverdiere M Lussier N et al Antifungal prophylaxis for

severely neutropenic chemotherapy recipients a meta analysis of

randomized-controlled clinical trials Cancer 2002 94 3230ndash46

101 Viscoli C Paesmans M Sanz M et al Association between

antifungal prophylaxis and rate of documented bacteremia in febrile

neutropenic cancer patients Clin Infect Dis 2001 32 1532ndash7

102 HughesWT Armstrong D BodeyGP et al 2002 guidelines for the

use of antimicrobial agents in neutropenic patients with cancerClin Infect

Dis 2002 34 730ndash51

103 Cornely OA Bohme A Buchheidt D et al Prophylaxis of invasive

fungal infections in patients with hematological malignancies and solid

tumorsmdashguidelines of the Infectious Diseases Working Party (AGIHO)

of the German Society of Hematology and Oncology (DGHO) Ann

Hematol 2003 82 Suppl 2 186ndash200

104 McNeil MM Nash SL Hajjeh RA et al Trends in mortality due to

invasivemycotic diseases in theUnitedStates 1980ndash1997Clin InfectDis

2001 33 641ndash7

105 KibblerCCSeatonSBarnesRA et alManagement and outcome

of bloodstream infections due to Candida species in England and Wales

J Hosp Infect 2003 54 18ndash24

106 Marchetti O Bille J Fluckiger U et al Fungal Infection Network of

Switzerland Epidemiology of candidemia in Swiss tertiary care hospitals

secular trends 1991-2000 Clin Infect Dis 2004 38 311ndash20

107 Gudlaugsson O Gillespie S Lee K et al Attributable mortality of

nosocomial candidemia revisited Clin Infect Dis 2003 37 1172ndash7

108 Ibanez-Nolla J Nolla-Salas M Leon MA et al Early diagnosis of

candidiasis in nonneutropenic critically ill patients J Infect 2004 48181ndash92

109 BlumbergHMJarvisWRSoucieJMetalRisk factors for candidal

bloodstream infections in surgical intensive care unit patients the NEMIS

prospective multicenter study The National Epidemiology of Mycosis

Survey Clin Infect Dis 2001 33 177ndash86

110 Pittet D Monod M Suter PM et al Candida colonization and

subsequent infections in critically ill surgical patients Ann Surg 1994

220 751ndash8

111 Sendid B Poirot JL Tabouret M et al Combined detection of

mannanaemia and antimannan antibodies as a strategy for the diagnosis

of systemic infectioncausedbypathogenicCandidaspeciesJMedMicro-

biol 2002 51 433ndash42

112 Bar W Hecker H Diagnosis of systemic Candida infections in

patients of the intensive care unit Significance of serum antigens and

antibodies Mycoses 2002 45 22ndash8

113 Calandra T Marchetti O Clinical trials of antifungal prophy-

laxis among patients undergoing surgery Clin Infect Dis 2004 39S185ndash92

114 Sypula WT Kale-Pradhan PB Therapeutic dilemma of flucona-

zole prophylaxis in intensive care Ann Pharmacother 2002 36 155ndash9

115 Pelz RK Hendrix CW Swoboda SM et al Double-blind placebo-

controlled trial of fluconazole to prevent candidal infections in critically ill

surgical patients Ann Surg 2001 233 542ndash8

116 Eggimann P Francioli P Bille J et al Fluconazole prophylaxis

prevents intraabdominal candidiasis in high-risk surgical patients Crit

Care Med 1997 27 1066ndash72

117 Swoboda SM Merz WG Lipsetta PA Candidemia the impact of

antifungal prophylaxis in a surgical intensive care unitSurg Infect20034345ndash54

118 Todd JC OrsquoNeal VG Grady KP et al Reduction of secondary

mycotic infections in the trauma intensivie care unit with fluconazole

J Trauma 1991 31 1722ndash27

119 Jacobs S Price Evans DA Tariq M et al Fluconazole improves

survival in septic shock a randomized double-blind prospective studyCrit

Care Med 2003 31 1938ndash46

120 Zervos EE Fink GW Norman JG et al Fluconazole increases

bactericidal activity of neutrophils through non-cytokine-mediated path-

way J Trauma 1996 41 465ndash70

121 AblesAZBlumerNAValainisGTetal Fluconazoleprophylaxis of

severe Candida infection in trauma and postsurgical patients a prospec-

tive double-blind randomised placebo-controlled trial Infect Dis Clin

Pract 2000 9 169ndash75

122 Kam LW Lin JD Management of systemic candidal infections in

the intensive care unit Am J Health Syst Pharm 2002 59 33ndash41

123 Rocco TR Reinert SE Simms HH Effects of fluconazole admin-

istration in critically ill patients analysis of bacterial and fungal resistance

Arch Surg 2000 135 160ndash5

124 Tortorano AM Caspani L Rigoni AL et al Candidosis in the inten-

sive care unit a 20-year survey J Hosp Infect 2004 57 8ndash13

125 EggimannPGarbino J Pittet DManagement ofCandida species

infections in critically ill patients Lancet Infect Dis 2003 3 772ndash85

Review

407

126 EggimannPGarbinoJPittetDEpidemiologyofCandida species

infections incritically ill non-immunosuppressedpatientsLancet InfectDis

2003 3 685ndash702

127 Martins MD Lozano-Chiu M Rex JH Declining rates of oropha-

ryngeal candidiasis and carriage of Candida albicans associated with

trends toward reduced rates of carriage of fluconazole-resistant C albi-

cans in human immunodeficiency virus-infected patients Clin Infect Dis

1998 27 1291ndash4

128 Powderly WG Finkelstein D Feinberg J et al A randomized trial

comparing fluconazole with clotrimazole troches for the prevention of fun-

gal infections in patients with advanced human immunodeficiency virus

infection NIAID AIDS Clinical Trials Group N Engl J Med 1995 332700ndash5

129 Leen CL Dunbar EM Ellis ME et al Once-weekly fluconazole to

prevent recurrenceof oropharyngeal candidiasis inpatientswithAIDSand

AIDS-related complex a double-blind placebo-controlled study J Infect

1990 21 55ndash60

130 Stevens DA Greene SI Lang OS Thrush can be prevented in

patients with acquired immunodeficiency syndrome and the acquired

immunodeficiency syndrome-related complex Randomized double-

blind placebo-controlled study of 100-mg oral fluconazole daily Arch

Intern Med 1991 151 2458ndash64

131 Just-Nubling G Gentschew G Meissner K Fluconazole prophy-

laxis of recurrent oral candidiasis inHIV-positive patientsEur JClinMicro-

biol Infect Dis 1991 10 917ndash21

132 Marriott DJ Jones PD Hoy JF et al Fluconazole once a week as

secondary prophylaxis against oropharyngeal candidiasis in HIV-infected

patients A double-blind placebo-controlled studyMed J Aust 1993 158312ndash16

133 Schuman P Capps L Peng G et al Weekly fluconazole for the

prevention ofmucosal candidiasis inwomenwithHIV infection A random-

ized double-blind placebo-controlled trial Terry Beirn Community Pro-

grams for Clinical Research on AIDSAnn InternMed 1997 126 689ndash96

134 Havlir DV DubeMPMcCutchan JA et al Prophylaxis with weekly

versus daily fluconazole for fungal infections in patients with AIDS Clin

Infect Dis 1998 27 1369ndash75

135 Pagani JL Chave JP Casjka C et al Efficacy tolerability and

development of resistance in HIV-positive patients treated with flucona-

zole for secondary prevention of oropharyngeal candidiasis a random-

ized double-blind placebo-controlled trial JAntimicrobChemother 2002

50 231ndash40

136 Vazquez JA Peng G Sobel JD et al Evolution of antifungal sus-

ceptibility amongCandidaspecies isolates recovered fromhuman immun-

odeficiency virus-infected women receiving fluconazole prophylaxis Clin

Infect Dis 2001 33 1069ndash75

137 Delfraissy JF Prise en charge therapeutique des patients infectespas le VIH Rapport Delfraissy Paris Flammarion 2004

138 DePauwBERaemaekers JMDonnelly JPet al Anopenstudyon

the safety and efficacy of fluconazole in the treatment of disseminated

Candida infections in patients treated for hematological malignancy Ann

Hematol 1995 70 83ndash7

139 Anaissie EJ Vartivarian SE Abi-Said D et al Fluconazole versus

amphotericin B in the treatment of hematogenous candidiasis a matched

cohort study Am J Med 1996 101 170ndash6

140 Anaissie EJ Darouiche RO Abi-Said D et al Management of

invasive candidal infections results of a prospective randomized multi-

center study of fluconazole versus amphotericin B and review of the

literature Clin Infect Dis 1996 23 964ndash72

141 Myoken Y Kyo T Kohara T et al Breakthrough fungemia caused

by azole-resistant Candida albicans in neutropenic patients with acute

leukemia Clin Infect Dis 2003 36 1496ndash7

142 Anttila VJ FarkkilaM JanssonSE et al Diagnostic laparoscopy in

patientswith acute leukemiaandsuspectedhepatic candidiasisEur JClin

Microbiol Infect Dis 1997 16 637ndash43

143 Anaissie E Bodey GP Kantarjian H et al Fluconazole therapy for

chronic disseminated candidiasis in patients with leukemia and prior

amphotericin B therapy Am J Med 1991 91 142ndash50

144 KauffmanCA BradleySFRossSC et al Hepatosplenic candidia-

sis successful treatment with fluconazole Am J Med 1991 91 137ndash41

145 Kontoyiannis DP Luna MA Samuels BI et al Hepatosplenic can-

didiasis A manifestation of chronic disseminated candidiasis Infect Dis

Clin North Am 2000 14 721ndash39

146 Graninger W Presteril E Schneeweiss B et al Treatment of

Candida albicans fungaemia with fluconazole J Infect 1993 26 133ndash46

147 Phillips P Shafran S Garber G et al Multicenter randomized trial

of fluconazole versus amphotericin B for treatment of candidemia in

non-neutropenic patients Canadian Candidemia Study Group Eur J

Clin Microbiol Infect Dis 1997 16 337ndash45

148 Rex JH Bennett JE Sugar AM et alA randomized trial comparing

fluconazolewithamphotericinB for the treatmentof candidemia inpatients

without neutropenia Candidemia Study Group and the National Institute

N Engl J Med 1994 331 1325ndash30

149 Abele-Horn M Kopp A Sternberg U et al A randomized study

comparing fluconazolewith amphotericinB5-flucytosine for the treatment

of systemic Candida infections in intensive care patients Infection 1996

24 426ndash32

150 Nguyen MH Peacock JE Jr Tanner DC et al Therapeutic

approaches in patients with candidemia Evaluation in a multicenter

prospective observational study Arch Intern Med 1995 155 2429ndash35

151 Rex JH Pappas PG Karchmer AW et al A randomized and

blinded multicenter trial of high-dose fluconazole plus placebo versus flu-

conazole plus amphotericin B as therapy for candidemia and its con-

sequences in non-neutropenic subjectsClin Infect Dis 2003 36 1221ndash8

152 Mora-Duarte J Betts R Rotstein C et al Comparison of

caspofungin and amphotericin B for invasive candidiasis N Engl J Med

2002 347 2020ndash9

153 Sugar AM Saunders C Diamond RD et al Successful treatment

of Candida osteomyelitis with fluconazole A noncomparative study of

two patients Diagn Microbiol Infect Dis 1990 13 517ndash20

154 Tang C Successful treatment of Candida albicans osteomyelitis

with fluconazole J Infect 1993 26 89ndash92

155 LafontAOliveAGelmanMet alCandidaalbicansspondylodisci-

tis and vertebral osteomyelitis in patients with intravenous heroin drug

addiction Report of 3 new cases J Rheumatol 1994 21 953ndash6

156 Hennequin C Bouree P Hiesse C et al Spondylodiskitis due to

Candida albicans report of two patients who were successfully treated

with fluconazole and review of the literature Clin Infect Dis 1996 23176ndash8

157 Jonnalagadda S VeerabaguMP Rakela J et alCandida albicans

osteomyelitis in a liver transplant recipient a case report and review of the

literature Transplantation 1996 62 1182ndash4

158 Rossel P Schonheyder HC Nielsen H Fluconazole therapy

inCandidaalbicansspondylodiscitisScandJ InfectDis199830 527ndash30

159 TurnerDLJohnsonSARuleSASuccessful treatmentof candidal

osteomyelitis with fluconazole following failure with liposomal ampho-

tericin B J Infect 1999 38 51ndash3

160 El-Zaatari MM Hulten K Fares Y et al Successful treatment of

Candida albicans osteomyelitis of the spine with fluconazole and surgical

debridement case report J Chemother 2002 14 627ndash30

161 Seravalli L Van Linthoudt D Bernet C et al Candida glabrata

spinal osteomyelitis involving two contiguous lumbar vertebrae a case

report and review of the literature Diagn Microbiol Infect Dis 2003 45137ndash41

162 Garbino J Schnyder I LewDP et al An unusual cause of vertebral

osteomyelitis Candida species Scand J Infect Dis 2003 35 288ndash91

163 TunkelARThomasCYWispelweyBCandidaprostheticarthritis

report of a case treated with fluconazole and review of the literature Am J

Med 1993 94 100ndash3

Review

408

164 CushingRD FulgenziWR Synovial fluid levels of fluconazole in a

patient with Candida parapsilosis prosthetic joint infection who had an

excellent clinical response J Arthroplasty 1997 12 950

165 Fukasawa N Shirakura K Candida arthritis after total knee

arthroplastymdasha case of successful treatment without prosthesis removal

Acta Orthop Scand 1997 68 306ndash7

166 Lerch K Kalteis T Schubert T et al Prosthetic joint infections with

osteomyelitis due to Candida albicans Mycoses 2003 46 462ndash6

167 Clancy CJ Nguyen MH Morris AJ Candidal mediastinitis an

emerging clinical entity Clin Infect Dis 1997 25 608ndash13

168 PetrikkosGSkiadaA SabatakouH et al Case report Successful

treatment of two cases of post-surgical sternal osteomyelitis due to

Candida krusei and Candida albicans respectively with high doses of

triazoles (fluconazole itraconazole) Mycoses 2001 44 422ndash5

169 Weers-Pothoff GHavermans JF Kamphuis J et alCandida tropi-

calis arthritis in a patient with acutemyeloid leukemia successfully treated

with fluconazole case report and review of the literature Infection 1997

25 109ndash11

170 Laatikainen L TuominenM vonDickhoff K Treatment of endoge-

nous fungal endophthalmitis with systemic fluconazole with or without

vitrectomy Am J Ophthalmol 1992 113 205ndash7

171 Borne MJ Elliott JH OrsquoDay DM Ocular fluconazole treatment of

Candidaparapsilosisendophthalmitis after failed intravitreal amphotericin

B Arch Ophthalmol 1993 111 1326ndash7

172 Zarbin MA Becker E Witcher J et al Treatment of presumed

fungal endophthalmitis with oral fluconazole Ophthalmic Surg Lasers

1996 27 628ndash31

173 WongVK TasmanWEagleRC et al BilateralCandida parapsilo-

sis endophthalmitis Arch Ophthalmol 1997 115 670ndash2

174 Kauffman CA Bradley SF Vine AK Candida endophthalmitis

associated with intraocular lens implantation efficacy of fluconazole ther-

apy Mycoses 1993 36 13ndash17

175 del Palacio A Cuetara MS Ferro M et al Fluconazole in the man-

agement of endophthalmitis in disseminated candidosis of heroin addicts

Mycoses 1993 36 193ndash9

176 Luttrull JK Wan WL Kubak BM et al Treatment of ocular fungal

infections with oral fluconazole Am J Ophthalmol 1995 119 477ndash81

177 Akler ME Vellend H McNeely DM et al Use of fluconazole in the

treatment of candidal endophthalmitis Clin Infect Dis 1995 20 657ndash64

178 Christmas NJ Smiddy WE Vitrectomy and systemic fluconazole

for treatment of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1996 27 1012ndash18

179 EssmanTFFlynnHWSmiddyWEet al Treatment outcomes in a

10-year study of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1997 28 185ndash94

180 Martinez-Vazquez C Fernandez-Ulloa J Bordon J et al Candida

albicans endophthalmitis in brown heroin addicts response to early vit-

rectomyprecededand followedbyantifungal therapyClin InfectDis1998

27 1130ndash3

181 Aleixo MJ Caldeira L Ferreira ML Candida albicans meningitis

clinical case J Infect 2000 40 191ndash2

182 InoueY YozuR Ueda T et al A case report ofCandida parapsilo-

sis endocarditis J Heart Valve Dis 1998 7 240ndash2

183 Isalska BJ Stanbridge TN Fluconazole in the treatment of candi-

dal prosthetic valve endocarditis BMJ 1988 297 178ndash9

184 Martino P Meloni G Cassone A Candidal endocarditis and treat-

ment with fluconazole and granulocyte-macrophage colony-stimulating

factor Ann Intern Med 1990 112 966ndash7

185 Roupie E Darmon JY Brochard L et al Fluconazole therapy of

candidal native valveendocarditisEur JClinMicrobiol InfectDis199110458ndash9

186 Hernandez JA Gonzalez-Moreno M Llibre JM et al Candidal

mitral endocarditis and long-term treatment with fluconazole in a patient

with human immunodeficiency virus infection Clin Infect Dis 1992 151062ndash3

187 Venditti MDeBernardis FMicozzi A et al Fluconazole treatment

of catheter-related right-sided endocarditis caused by Candida albicans

and associated with endophthalmitis and folliculitis Clin Infect Dis 1992

14 422ndash6

188 Wallbridge DR McCartney AC Richardson MD Fluconazole in

the treatment ofCandidaprosthetic valveendocarditisMycoses199336259ndash61

189 Otaki M Kitamura N Candida prosthetic valve endocarditis An

autopsy review Int Surg 1993 78 252ndash3

190 Czwerwiec FS Bilsker MS Kamerman ML et al Long-term sur-

vival after fluconazole therapy of candidal prosthetic valve endocarditis

Am J Med 1993 94 545ndash6

191 Thakur RK Skelcy KM Kahn RN et al Successful treatment of

Candida prosthetic valve endocarditis with a combination of fluconazole

and amphotericin B Crit Care Med 1994 22 712ndash14

192 Cancelas JA Lopez JCabezudoE et al Native valve endocarditis

due toCandida parapsilosis a late complication after bonemarrow trans-

plantation-related fungemia Bone Marrow Transplant 1994 13 333ndash4

193 Zahid MA Klotz SA Hinthorn DR Medical treatment of recurrent

candidemia in a patient with probable Candida parapsilosis prosthetic

valve endocarditis Chest 1994 105 1597ndash8

194 Wells CJ Leech G Lever AM et al Treatment of native valve

Candida endocarditis with fluconazole J Infect 1995 31 233ndash5

195 Gilbert HM Peters ED Lang SJ et al Successful treatment of

fungal prosthetic valve endocarditis case report and review Clin Infect

Dis 1996 22 348ndash54

196 Nguyen MH Nguyen ML Yu VL et al Candida prosthetic valve

endocarditis prospective study of six cases and review of the literature

Clin Infect Dis 1996 22 262ndash7

197 Lejko-Zupanc T Kozelj M A case of recurrent Candida parapsilo-

sis prosthetic valve endocarditis cure bymedical treatment alone J Infect

1997 35 81ndash2

198 Joly V BelmatougN Leperre A et al Pacemaker endocarditis due

to Candida albicans case report and review Clin Infect Dis 1997 251359ndash62

199 Rex JH Walsh T Sobel JD et al Practice guidelines for the treat-

mentof candidiasis InfectiousDiseasesSocietyofAmericaClin InfectDis

2000 30 662ndash78

200 Baddour LM Long-term suppressive therapy for Candida para-

psilosis-induced prosthetic valve endocarditis Mayo Clin Proc 1995

70 773ndash5

201 Melgar GR Nasser RM Gordon SM Fungal prosthetic valve

endocarditis in 16 patients An 11-year experience in a tertiary care hos-

pital Medicine 1997 76 94ndash103

202 Dupont H Paugam-Burtz C Muller-Serieys C et al Predictive

factors of mortality due to polymicrobial peritonitis with Candida isolation

in peritoneal fluid in critically ill patients Arch Surg 2002 137 1341ndash6

203 Lee SC FungCP ChenHY et alCandida peritonitis due to peptic

ulcer perforation incidence rate risk factors prognosis and susceptibility

to fluconazole and amphotericin B Diagn Microbiol Infect Dis 2002 4423ndash7

204 Levine J Bernard DB Idelson BA et al Fungal peritonitis compli-

cating continuous ambulatory peritoneal dialysis successful treatment

with fluconazole a new orally active antifungal agent Am J Med 1989

86 825ndash7

205 Michel C Courdavault L al Khayat R et al Fungal peritonitis in

patients on peritoneal dialysis Am J Nephrol 1994 14 113ndash20

206 WangAYYuAWLi PKet al Factors predicting outcomeof fungal

peritonitis in peritoneal dialysis analysis of a 9-year experience of fungal

peritonitis in a single center Am J Kidney Dis 2000 36 1183ndash92

207 Hawkins JL Baddour LM Candida lusitaniae infections in the era

of fluconazole availability Clin Infect Dis 2003 36 14ndash18

Review

409

208 KauffmanCAVazquezJASobel JDetal Prospectivemulticenter

surveillance study of funguria in hospitalized patients The National Insti-

tute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group

Clin Infect Dis 2000 30 14ndash18

209 Sobel JD Kauffman CA McKinsey D et al Candiduria a random-

ized double-blind study of treatment with fluconazole and placebo The

National Institute of Allergy and Infectious Diseases (NIAID) Mycoses

Study Group Clin Infect Dis 2000 30 19ndash24

210 LundstromTSobel JNosocomial candiduria a reviewClin Infect

Dis 2001 32 1602ndash7

211 Kaufman D Boyle R Hazen KC et al Fluconazole prophylaxis

against fungal colonization and infection in preterm infants N Engl J

Med 2001 345 1660ndash6

212 Kicklighter SD Springer SC Cox T et al Fluconazole for the pro-

phylaxis against candidal rectal colonization in the very low birth weight

infant Pediatrics 2001 107 293ndash8

213 McGuire W Clerihew L Austin N Prophylactic intravenous anti-

fungal agents to prevent mortality and morbidity in very low birth weight

infants Cochrane Database Syst Rev 2004 CD003850

214 Agarwal JBansalSMalikGKetal Trends inneonatal septicemia

emergence of non-albicans Candida Indian Pediatr 2004 41 712ndash15

215 FasanoCOrsquoKeefe JGibbsD Fluconazole treatment of neonates

and infants with severe fungal infections not treatable with conventional

agents Eur J Clin Microbiol Infect Dis 1994 13 351ndash4

216 Wainer S Cooper PA Gouws H et al Prospective study of flu-

conazole therapy in systemicneonatal fungal infectionPediatr InfectDis J

1997 16 763ndash7

217 Huang YC Lin TY Lien RI et al Fluconazole therapy in neonatal

candidemia Am J Perinatol 2000 17 411ndash15

218 Huttova M Hartmanova I Kralinsky K et al Candida fungemia in

neonates treated with fluconazole report of forty cases including eight

with meningitis Pediatr Infect Dis J 1998 17 1012ndash15

219 Gurpinar AN Balkan E Kilic N et al Fluconazole treatment of

neonates and infants with severe fungal infections J Int Med Res 1997

25 214ndash18

220 Driessen M Ellis JB Muwazi F et al The treatment of systemic

candidiasis in neonates with oral fluconazole Ann Trop Pediatr 1997 17263ndash71

221 Driessen M Ellis JB Cooper PA et al Fluconazole vs

amphotericin B for the treatment of neonatal fungal septicemia

a prospective randomized trial Pediatr Infect Dis J 1997 151107ndash12

222 Marr B Gross S Cunningham C et al Candidal sepsis and

meningitis in a very-low-birth-weight infant successfully treated with flu-

conazole and flucytosine Clin Infect Dis 1994 19 795ndash6

223 Oleinik EM Della-Latta P Rinaldi MG et al Candida lusitaniae

osteomyelitis in a premature infant Am J Perinatol 1993 10 313ndash15

224 Mondal RK Singhi SC Chakrabarti A Randomized comparison

between fluconazole and itraconazole for the treatment of candidemia in a

pediatric intensive care unit a preliminary study Pediatr Crit Care Med

2004 5 561ndash5

225 Viscoli C Castagnola E Fioredda F et al Fluconazole in the treat-

ment of candidiasis in immunocompromised children Antimicrob Agents

Chemother 1991 35 365ndash7

226 Decruyenaere J Colardyn F Vogelaers D et al Combined use of

fluconazole and selective digestive decontamination in the prevention of

fungal infection after adult liver transplantation Transplant Proc 1995 273515ndash16

227 Koh LP Kurup A Goh YT et al Randomized trial of fluconazole

versus low-dose amphotericin B in prophylaxis against fungal infections in

patients undergoing hematopoietic stem cell transplantationAmJHema-

tol 2002 71 260ndash7

228 Gluckman E Esperou-Bourdeau H Ribaud P et al Comparaison

entre le fluconazole et le ketoconazole pour la prophylaxie des infections

fongiques chez les patients traites par greffe de moelle allogenique Cah

Oncol 1993 2 167ndash9

Review

410

Table

10

Stu

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naz

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HIV

-in

fect

edp

atie

nts

Ref

eren

ceS

tud

yd

esig

nR

egim

en

Du

rati

on

of

trea

tmen

t

Nu

mb

er

of

pat

ien

tsR

ate

of

infe

ctio

ns

Lee

net

al

12

9R

D

B

SC

FL

Cp

o1

50

mg

wee

kv

ersu

sp

lace

bo

24

wee

ks

14

22

10

0

Ste

ven

set

al

13

0R

N

B

SC

FL

Cp

o2

00

mg

day

ver

sus

pla

ceb

o1

2w

eek

s1

20

13

62

Just

-Nu

bli

nget

al

13

1R

N

B

SC

FL

Cp

o5

0m

gd

ayo

r1

00

mg

day

6m

on

ths

18

11

ver

sus

pla

ceb

o1

92

1

21

95

Mar

rio

ttet

al

13

2R

D

B

PC

S

CF

LC

po

15

0m

gw

eek

ver

sus

pla

ceb

o6

mo

nth

s3

54

2

38

96

Sch

um

anet

al

13

3R

D

B

PC

M

CF

LC

20

0m

gw

eek

ver

sus

pla

ceb

o2

9m

on

ths

16

24

4

16

15

8

Hav

liret

al

13

4R

D

B

MC

FL

C4

00

mg

wee

kv

ersu

s2

00

mg

day

52

8d

ays

31

82

0

31

81

2

Pag

aniet

al

13

5R

D

B

PC

S

CF

LC

po

15

0m

gw

eek

ver

sus

pla

ceb

o3

7m

on

ths

67

71

61

71

90

(Plt00001)

Rr

andom

ized

DB

double

bli

ndP

Cp

lace

bo

contr

oll

edS

Cs

ingle

centr

eM

Cm

ult

icen

tre

FL

Cf

luco

naz

ole

poo

ral

OP

Co

rophar

yngea

lcan

did

iasi

sO

Co

eso

ph

agea

lcan

did

iasi

sV

alu

esg

iven

inb

old

face

are

stat

isti

call

ysi

gnif

ican

t

Review

398

Table

11

Stu

die

so

nfl

uco

naz

ole

ascu

rati

ve

trea

tmen

tam

on

gn

on

-neu

tro

pen

icp

atie

nts

Ref

eren

ceS

tud

yd

esig

nK

ind

of

infe

ctio

nR

egim

en

Du

rati

on

of

trea

tmen

t

Nu

mb

ero

f

pat

ien

tsE

val

uat

ion

item

sE

ffic

acy

Ph

illi

pset

al

14

7R

M

C

PC

can

did

aem

iaF

LC

40

0m

gd

ayiv

ver

sus

AM

B

06

mg

kg

day

iv

4ndash

8w

eek

s5

0

53

clin

ical

mic

robio

logic

al

6m

on

ths

surv

ival

FL

C5

7

AM

B6

2

An

aiss

ieet

al

14

0R

M

C

PC

inv

asiv

e

can

did

iasi

s

FL

C4

00

mg

day

iv

ver

sus

AM

B

25

ndash5

0m

gd

ayiv

9d

ays

75

67

clin

ical

mic

robio

logic

alE

OT

FL

C66

AM

B6

4

An

aiss

ieet

al

13

9O

S

Cca

nd

idae

mia

FL

C2

00

ndash6

00

mg

day

ver

sus

AM

B

03

ndash1

2m

gk

gd

ay

13

day

s

10

day

s

45

45

clin

ical

mic

robio

logic

al

D0

D

5

EO

T

FL

C7

3

AM

B7

1

Ab

ele-

Ho

rnet

al

14

9R

S

Cin

vas

ive

can

did

iasi

s

FL

C2

00

mg

day

iv

ver

sus

AM

B1

ndash1

5m

gk

g

ever

yo

ther

day

+

5F

C3middot

25

gd

ay

14

day

s3

6

36

clin

ical

mic

robio

logic

alE

OT

FL

C64

AM

B+

5F

C6

3

Ng

uy

enet

al

15

0O

M

C

PC

can

did

aem

iaF

LC

10

0ndash

80

0m

gd

ay

ver

sus

AM

B

13

day

s6

7

22

7

dea

thE

OT

no

dif

fere

nce

inm

ort

alit

yat

D+

7D

+1

4

D+

21

Rex

etal

14

8R

D

B

MC

can

did

aem

iaF

LC

40

0m

gd

ayiv

ver

sus

AM

B

06

mg

kg

day

iv

4ndash

8w

eek

s1

03

10

3

clin

ical

mic

robio

logic

alW

12

FL

C70

AM

B7

9

Rr

and

om

ized

D

Bd

ou

ble

bli

nd

S

Bs

ing

leb

lin

dP

Cp

lace

bo

con

tro

lled

S

Cs

ing

lece

ntr

eM

Cm

ult

icen

tre

FL

Cf

luco

naz

ole

A

MB

am

ph

ote

rici

nB

5

FC

flu

cyto

sin

ep

oo

ral

Dd

ayW

wee

kE

OT

en

do

ftr

eatm

ent

iv

intr

aven

ou

s

Review

399

response or death could be found In 1996 Anaissie et al139 com-pared the same drugs in cancer patients with candidiasis andenrolled 90 patients Doses of both fluconazole and amphotericinwere highly variable (fluconazole 200ndash600 mgday amphotericinB 03ndash12 mgkgday) The two cohorts were well matched andresponse rates at day 5 for each cohort were similar overallresponse rates were slightly better for fluconazole and therewere significantly fewer toxic effects in the fluconazole group

A more recent comparison of fluconazole versus fluconazoleplus amphotericin B in non-neutropenic subjects compared 800mgday of fluconazole versus the same dose plus 07 mgkgdayof amphotericin B in a randomized blinded multicentre trial invol-ving 219 patients151 Success rates were slightly higher and therewas a faster clearance rate of candidaemia in the combination groupcompared with fluconazole alone This suggests that the two drugsare not antagonistic and may perhaps act synergistically

Although fluconazole may be the preferred agent in non-neu-tropenic patients because of its low toxicity the recent introductionof caspofungin challenges this place particularly as it has a broaderspectrum of action A randomized study comparing caspofunginversus amphotericin B for the treatment of candidaemia in bothneutropenic and non-neutropenic patients has been completed butthere is no direct comparison with fluconazole152 Results of aprospective randomized controlled multicentre trial comparinganidulafungin a new echinocandin and fluconazole in patientswith candidaemia should be available soon

Fluconazole for the treatment of specific Candida

organ infections

All randomized studies using fluconazole to date have been under-taken in oesophageal candidiasis or candidaemia none in Candidaorgan infection although some patients with invasive candidiasishave been included in the randomized studies Therefore the datapresented here come from non-comparative open-label studies

Osteoarticular infections due to Candida sp

Very few data are available on the efficacy of fluconazole as firstline therapy in osteoarticular infections due to Candida sp Someobservations associated with spondylodiscitis have been publishedand have been summarized in Table 12153ndash162 Fluconazole (200ndash400 mgday initially gt2 months) proved to be efficacious in threecases of knee infections due to C parapsilosis163ndash165 A prostheticjoint infection and osteomyelitis of the knee due toC albicanswerecured with high doses of 800 mgday of fluconazole for 2 months incombination with repeated surgical debridement after a 10 daycourse of fluconazole 400 mgday which seemed to be ineffi-cient166 Fluconazole (400ndash800 mgday for 6 months) was alsoeffective for the treatment ofC albicans post-surgical mediastinitisin two cases167168 Fluconazole (400 mgday for 7 months) suc-cessfully treated an old patient with acute myeloid leukaemia whopresented with C tropicalis arthritis of the knee169 The latestIDSA guidelines recommend surgical debridement and initialcourse of amphotericin B for 2ndash3 weeks followed by fluconazolefor a total duration of 6ndash12 months57

Endophthalmitis due to Candida sp

A combination of partial or complete vitrectomy intraocularamphotericin B and antifungal drugs is the usual therapeuticapproach to Candida sp eye infections Several documented T

able

12

Rep

ort

so

fp

atie

nts

wit

hsp

on

dy

lod

isci

tis

du

eto

Candida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Lo

cali

zati

on

of

infe

ctio

n

Candida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Do

seo

ffl

uco

naz

ole

(mg

day

)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y

(fo

llo

w-u

pd

ura

tio

n)

Gar

bin

oet

al

16

2lu

mb

arCalbicans

14

00

3m

on

ths

(rel

apse

)

then

6m

on

ths

ndashre

cov

ery

(16

mo

nth

s)

lum

bar

Ctropicalis

18

00

foll

ow

edb

yit

raco

naz

ole

reco

ver

y(4

mo

nth

s)

Ser

aval

liet

al

16

1lu

mb

arCglabrata

18

00

3w

eek

sre

pla

ced

by

AM

B(7

0d

ays)

then

lip

idco

mp

lex

(56

day

s)

fail

ure

wit

hfl

uco

naz

ole

then

reco

ver

y(1

6m

on

ths)

El-

Zaa

tariet

al

16

0d

ors

alCalbicans

14

00

3m

on

ths

ndashre

cov

ery

(1y

ear)

Tu

rner

etal

15

9d

ors

o-l

um

bar

Calbicans

12

00

(1m

on

th)

then

10

01

2m

on

ths

afte

rfa

ilu

reo

fA

MB

li

po

som

al

AM

Ban

d5

FC

(9w

eek

s)

reco

ver

y(3

yea

rs)

Ro

ssel

etal

15

8d

ors

alCalbicans

14

00

(14

day

s)th

en2

00

7m

on

ths

afte

rfa

ilu

reo

fA

MB

(21

day

s)re

cov

ery

(1y

ear)

Jon

nal

agad

daet

al

15

7d

ors

alCalbicans

12

00

6m

on

ths

AM

B(3

g)

+5

FC

reco

ver

y(8

mo

nth

s)

Hen

neq

uin

etal

15

6lu

mb

arCalbicans

14

00

6m

on

ths

ndashre

cov

ery

(47

mo

nth

s)

lum

bar

C

alb

ican

s1

20

06

mo

nth

sndash

reco

ver

y(1

7m

on

ths)

Laf

on

tet

al

15

5lu

mb

arCalbicans

14

00

4w

eek

sndash

reco

ver

y(1

8m

on

ths)

Tan

get

al

15

4d

ors

alCalbicans

12

00

1y

ear

ndashre

cov

ery

(16

mo

nth

s)

Su

gar

etal

15

3d

ors

alan

dlu

mb

arCtropicalis

11

00

ndash1

50

1y

ear

AM

B(3

80

mg

)re

cov

ery

(26

mo

nth

s)

AM

B

amphote

rici

nB

5F

C

flucy

tosi

ne

Review

400

clinical cases reported the efficacy of fluconazole alone or incombination with other treatments in cases of endophthalmitisdue to Candida spp16170ndash173 Finally several recent series con-firmed fluconazole efficacy in cases of severe ocular infectionsdue to susceptible Candida sp in non-neutropenic patients174ndash180

Their results are summarized in Table 13 Most cases are due toC albicans and fluconazole-resistant species causing endoph-thalmitis is extremely rare On the basis of these data the IDSArecommends the use of fluconazole in this indication particularlyas follow-up therapy58

Meningitis due to Candida sp

Very few data exist on fluconazolersquos efficacy for the initial treat-ment of Candida sp meningitis in adults although this drug has avery good CSF penetration Oral fluconazole (800 mgday for3 months then 200 mgday) was successful for the treatment ofa C albicans meningitis in an HIV-infected patient with a CD4 cellcount of 35 cellsmm3 who refused intravenous therapy181

Endocarditis due to Candida sp

No series has documented the efficacy of fluconazole in endocard-itis due to Candida sp Only a few clinical cases have been pub-lished and most of these are summarized in Table 14182ndash198 Thesecases illustrate the efficacy of fluconazole (sometimes with nosurgical treatment) in endocarditis due to C albicans and alsoin endocarditis related to some non-albicans Candida spp espe-cially C parapsilosis However no study has demonstrated thesuperiority of fluconazole over amphotericin B in this indicationand there are insufficient data to recommend fluconazole as the firstline treatment for endocarditis due to Candida spp58199 Theechinocandins might have a place as primary therapy in thesecases Fluconazole (200ndash400 mgday) is often employed as partof a long-term suppressive regimen especially if valve replacementis not possible because of the high propensity for delayed relapse ofcandidal endocarditis200201

Peritonitis due to Candida sp

Peritonitis due to Candida sp may develop in patients with peri-toneal dialysis catheters or in those with surgical or traumaticinjury to the gut wall In this latter situation Candida spp areusually part of a polymicrobial infection Isolation of Candidaby direct examination of peritoneal fluid is an independent factorfor a severe outcome202 and recent small studies suggest thatprompt effective adequate and safe antifungal therapy shouldbe given in all cases of Candida sp peritonitis in order to lowerthe mortality rate and shorten the hospital stay113116 In a recentstudy of 23 cases secondary to peptic ulcer perforation the mor-tality rate in patients receiving fluconazole (200 mg intravenouslytwice daily for 2ndash4 weeks) was high (five of eight cases) probablyrelated to inadequate or too late initiation of antifungal therapy203

Some cases showing fluconazole efficacy have been reported inpatients with continuous ambulatory peritoneal dialysis eitheralone or in combination with flucytosine204ndash207 Catheter removalis crucial in these cases

Urinary infections due to Candida spp

Candida is by far the most frequent agent of urinary fungal infec-tions The line between colonization and real infection is generallyblurred Candiduria usually present as nosocomial infections T

able

13

Rep

ort

so

fp

atie

nts

wit

hen

do

ph

thal

mit

isd

ue

toCandida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Met

ho

do

log

y

of

stu

dy

Candida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Do

seo

f

flu

con

azo

le(m

gd

ay)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y

(fo

llo

w-u

pd

ura

tio

n)

Mar

tin

ez-V

azq

uez

etal

18

0p

rosp

ecti

ve

Calbicans

11

40

02

ndash8

wee

ks

AM

Biv

(n=

9)

or

no

trea

tmen

t(n

=1

)u

nti

l

vit

rect

om

y(n

=1

0

2ndash

18

0

day

saf

ter

dia

gn

osi

s)

91

1(6

mo

nth

s)

Ess

man

etal

17

9re

tro

spec

tiv

eCalbicansCtropicalis

5u

nsp

ecif

ied

un

spec

ifie

dv

itre

cto

myndash

loca

lA

MB

55

(25

ndash1

15

mo

nth

s)

Ch

rist

mas

etal

17

8p

rosp

ecti

ve

CalbicansCtropicalis

51

00

ndash2

00

3ndash

6w

eek

sv

itre

cto

my

55

(4ndash

11

mo

nth

s)

Ak

leret

al

17

7re

tro

spec

tiv

eu

nsp

ecif

ied

6to

tal

med

ian

do

se

=9

97

5m

g

med

ian

=5

2d

ays

AM

Biv

lt5

00

mg

+

vit

rect

om

y

1

56

re

lap

se

1(pound

6w

eek

s)

Lu

ttru

llet

al

17

6re

tro

spec

tiv

eCalbicans

(n=

2)

un

spec

ifie

d(n

=2

)

42

00

ndash4

00

4w

eek

s(n

=3

)v

itre

cto

my

1

44

(3ndash

25

mo

nth

sn

=3

)

del

Pal

acio

etal

17

5re

tro

spec

tiv

eCalbicans

74

00

(1d

ay)

then

20

03

wee

ks

ndash6

7(v

itre

cto

my

refu

sal

in

1p

atie

nt)

(Dagger6

mo

nth

s)

Kau

ffm

anet

al

17

4re

tro

spec

tiv

e

len

sim

pla

nts

Cparapsilosis

44

00

(20

0in

pat

ien

ts

wit

hre

nal

fail

ure

)

1y

ear

fail

ure

of

loca

lA

MB

rela

pse

ifn

ole

ns

abla

tio

n

(2y

ears

afte

rst

op

pin

g)

AM

B

amphote

rici

nB

iv

in

trav

enous

Review

401

Table

14

Rep

ort

so

fp

atie

nts

wit

hen

do

card

itis

du

eto

Candida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Val

vu

lar

inv

olv

emen

tCandida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Dose

of

fluco

naz

ole

(mg

day

)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y(f

oll

ow

-up

du

rati

on

)

Ino

ueet

al

18

2ao

rtic

val

ve

Cparapsilosis

16

00

then

40

01

8m

on

ths

surg

ery

reco

ver

y(1

8m

on

ths)

Lej

ko

-Zu

pan

cet

al

19

7m

itra

lp

rost

hes

isCparapsilosis

14

00

(14

day

s)th

en1

00

8m

on

ths

AM

B(3

9g

)A

BC

D

(15

g)

no

rep

lace

men

t

reco

ver

y(gt

3y

ears

)

Joly

etal

19

8p

acem

aker

Calbicans

14

00

(6d

ays)

then

20

07

mo

nth

ssu

rger

yre

cov

ery

(18

mo

nth

s)

Ng

uy

enet

al

19

6ao

rtic

pro

sth

esis

Calbicans

14

00

then

20

04

5y

ears

AM

B+

5F

C

12

wee

ks

no

rep

lace

men

t

reco

ver

y(5

5y

ears

)

Gil

ber

tet

al

19

5ao

rtic

pro

sth

esis

Calbicans

12

00

8m

on

ths

surg

ery

AM

B(2

g)

+

5F

C

40

day

s

reco

ver

y(9

mo

nth

s)

Wel

lset

al

19

4m

itra

lan

dtr

icu

spid

val

ves

Calbicans

12

00

ndash4

00

(14

day

s)

then

40

0th

en5

0

65

mo

nth

s

(40

0m

g)

and

10

mo

nth

s

(50

mg

)

no

rep

lace

men

tre

cov

ery

(45

yea

rs)

Zah

idet

al

19

3m

itra

lv

alv

e

(pro

bab

le)

Cparapsilosis

14

00

18

mo

nth

sA

MB

(5g

)+

5F

C

ket

oco

naz

ole

(80

0m

gd

ay

4m

on

ths)

no

rep

lace

men

t

reco

ver

y(5

yea

rs)

Can

cela

set

al

19

2m

itra

lv

alv

eCparapsilosis

12

00

4m

on

ths

surg

ery

A

MB

(2g

)re

cov

ery

(4m

on

ths)

Th

aku

ret

al

19

1ao

rtic

pro

sth

esis

Calbicans

12

00

6w

eek

sA

MB

(30

mg

day

)

6w

eeks

no

repla

cem

ent

reco

ver

y(2

6m

on

ths)

Czw

erw

iecet

al

19

0ao

rtic

pro

sth

esis

Cparapsilosis

14

00

26

mo

nth

sA

MB

(72

5m

g)

no

rep

lace

men

t

reco

ver

y(2

6m

on

ths)

Ota

kiet

al

18

9m

itra

lp

rost

hes

isCparapsilosis

1u

nsp

ecif

ied

68

day

sn

ore

pla

cem

ent

fail

ure

(dea

thd

ue

toce

reb

ral

hae

mo

rrh

age

and

fev

er)

Wal

lbri

dg

eet

al

18

8m

itra

lp

rost

hes

isCparapsilosis

12

00

-40

0gt

7w

eek

sA

MB

(30

0m

g)

no

rep

lace

men

t

reco

ver

y(6

mo

nth

s)

Ven

dit

tiet

al

18

7in

tera

tria

lse

ptu

mCalbicans

12

00

(28

day

s)th

en6

00

(11

day

s)th

en4

00

6m

on

ths

no

rep

lace

men

tre

cov

ery

(14

mo

nth

s)

Her

nan

dez

etal

18

6m

itra

lv

alv

eCalbicans

12

00

3m

on

ths

AM

Bfa

ilu

ren

o

rep

lace

men

t

imp

rov

emen

t(3

mo

nth

s)

Ro

up

ieet

al

18

5ao

rtic

val

ve

Ctropicalis

14

00

50

day

sn

ore

pla

cem

ent

reco

ver

y(1

1m

on

ths)

Mar

tin

oet

al

18

4in

tera

tria

lse

ptu

mCparapsilosis

13

mg

kg

(7d

ays)

then

6m

gk

g

gt3

mo

nth

sG

M-C

SF

(gt6

wee

ks)

no

rep

lace

men

t

reco

ver

y(5

mo

nth

s)

Isal

skaet

al

18

3m

itra

lp

rost

hes

isCparapsilosis

11

00

ndash2

00

11

mo

nth

sn

ore

pla

cem

ent

reco

ver

y(1

yea

r)

AM

B

amph

ote

rici

nB

5

FC

fl

ucy

tosi

ne

AB

CD

am

ph

ote

rici

nB

coll

oid

ald

isp

ersi

on

G

M-C

SF

g

ran

ulo

cyte

ndashm

on

ocy

teco

lon

y-s

tim

ula

tin

gfa

cto

r

Review

402

favoured by indwelling urinary catheters immunosuppressivedrugs or antibiotic prescriptions diabetes mellitus and extremeages C albicans is involved in half of the cases followed byC glabrata in 15 of the cases In 10 of cases infection involvesmore than one species208 Fluconazole achieves a 10 times higherconcentration in urine than in blood with powerful effect even onCglabrata infections Therefore it represents a first line treatment ofany Candida urinary tract infection

In a randomized placebo-controlled multicentre study amongpatients with asymptomatic candiduria Sobel et al209 found thatfluconazole (200 mgday) hastened the time to negative resultsof urine cultures However the rate of negative urine cultures2 weeks after the end of therapy was similar in the fluconazole-and placebo-treated groups showing the minimal utility of treat-ment in that setting Indeed asymptomatic candiduria should betreated only in high-risk situations namely patients with neutrope-nia infants with low birth weight patients with renal allografts andpatients who will undergo urologic manipulations (recommenda-tion of grade B-III from the IDSA) The optimal regimen in thatsetting is not known Short courses regimen are not recommendedand therapy for 1ndash2 weeks should be efficient

Ascending pyelonephritis treatment should also include ade-quate urinary drainage and removal of obstructive fungusballs210 Urinary tract devices should be optimally removed orat least replaced

Haematogenous renal involvement should be treated with high-dose parenteral fluconazole (6 mgkgday) in accordance with therecently published IDSA guidelines57

Fluconazole in childreninfants

No specific approval of fluconazole has been obtained inyoung children before the age of 6 months but a few studieshave evaluated its use in several settings

Prophylaxis of systemic candidiasis in neonates

Few studies have focused on the use of fluconazole as a prophy-lactic agent against invasive candidiasis in neonates Kaufmanet al211 demonstrated in 2001 the efficacy and safety of flucona-zole (3 mgkg every 3 days during the first 2 weeks then every2 days during the following 2 weeks and then every day until thesixth week of life) in extremely low birth weight and high-riskinfants (lt1000 g) in preventing both colonization and invasivefungal infection High risk was defined as the presence of a centralvascular catheter or endotracheal tube Indeed among the 50infants randomly assigned to fluconazole the rate of colonization(22) was significantly lower than in the 50 placebo-treated ones(60) no invasive fungal infection developed in the fluconazolegroup compared with a 20 rate of infection in the placebo groupNo adverse effect of fluconazole was documented

Kicklighter et al212 similarly observed the safety of fluconazoleat 6 mgkg (for 6 weeks) and its efficacy among neonates with lowbirth weight (lt1500 g) in the prevention of rectal colonization(however occurrence of invasive candidiasis was similar inboth groups) A Cochrane review of fluconazole prophylaxis inpreterm infants demonstrated a reduced risk of invasive infection(related risk 020) and mortality (related risk 044) in fluconazole-treated patients compared with placebo-treated patients213

Although concerns about resistance to azoles have been raised

the vast majority ofCandida spp strains have remained susceptibleto fluconazole over the past decade in this population40

Fluconazole in systemic candidiasis in childreninfants

Neonatal candidaemia Candidaemia is a major cause of sepsis inneonatal ICU representing up to 16 of all sepsis cases Therelated mortality rate is high often nearly 50214 Most casesare related to C albicans and C parapsilosis with a recent risein cases related to C tropicalis The main risk factors for invasivecandidiasis among neonates are low birth weight intravascularcatheters intratracheal intubation total parenteral nutrition andadministration of intralipid solution and recent administration ofbroad-spectrum antibiotics and corticosteroids10

Treatment with amphotericin B and 5-flucytosine has been thegold standard for years However amphotericin B has some seriousside effects which makes it mandatory to consider its use in thatsetting With good profile of tolerance good diffusion in all tissuesand body fluids and reliable oral absorption fluconazole has beenstudied as an alternative (see Table 15) In 1994 Fasano et al215

reported the compassionate use of fluconazole among 40 new-borns including 11 who presented with Candida sp meningitisThey were treated with a mean daily dosage of 5 mgkgday for amean duration of 26 days Of the 32 patients with evaluable out-come 31 experienced clearance of infection Other studies haveconfirmed these results in the recent years11216ndash220 In a multicen-tre prospective randomized study Driessen et al220 compared theefficacy and safety of either amphotericin B ndash 5-flucytosine orfluconazole (oral or intravenous dose of 10 mgkg as initialdose and then 5 mgkgday) in neonates with candidaemia Inthe fluconazole group 812 (67) survived versus 611 (55) inthe other group220 Among the four patients who died in the flu-conazole group two had treatment failure versus one in the ampho-tericin B group Cytolytic hepatitis was less frequent in thefluconazole-treated group Two isolated case reports also suggestthat the association of fluconazole and flucytosine might be syn-ergistic in the treatment of neonatal candidaemia222223

Very recently Mondal et al229 compared the efficacy and safetyof oral itraconazole versus oral fluconazole (both doses of 10 mgkgday) in newborns and paediatric patients with candidaemiaSimilar cure rate (81 and 82) mortality rate (95 and 135)and number of side effects were observed224 Fluconazole thusappears as a safe and effective systemic antifungal agent in thesetting of neonatal candidiasis

Children with systemic candidiasis Excluding the setting of neo-natal candidiasis very few studies have however focused on thepaediatric population when studying the efficiency of fluconazolefor the treatment of invasive candidiasis

In 1991 Viscoli et al reported the outcome of 24 immunocom-promised children treated with fluconazole (6 mgkgday) for 34episodes of proven invasive candidiasis A total of 3034 clinicaland microbiological cures were achieved Two patients with fun-gaemia due toC parapsilosis required an increase in dosage of up to12 mgkg Transient drug-related increases of liver transaminasesoccurred in two cases (6)225 In 1994 Fasano et al reported theoutcome of 63 children with AIDS cancer or transplantationprospectively receiving fluconazole as compassionate treatment(dose regimen ranging from 016 to 11 mgkgday mean 34 mgkgday)215 Half of them had fungaemia while the others hadrespiratory urinary tract or superficial oropharyngeal infections

Review

403

Clinical cure or improvement was achieved in 5263 (83) andpathogen eradication was achieved in 4359 (73)17 Huttovaet al218 reported in 1998 the outcome of 10 children withnosocomial fungal meningitis including 8 cases of candidal men-ingitis treated using fluconazole Five of them survived with clinicaland microbiological cure

Conclusions

Almost 15 years after its launch fluconazole remains a cornerstoneof antifungal prophylaxis and therapy of invasive candidiasis It hasan excellent pharmacokinetic and safety profile even in debilitatedpatients with good tissue penetration and a lack of major druginteractions particularly with immunosuppressive agents It can beprescribed in patients with renal failure if daily dosages are adaptedto the creatinine serum level Its spectrum of antimicrobial efficacyis reasonable and it remains active against most intrinsically sus-ceptible Candida spp encountered in systemic disease with lt5of C albicans resistant to fluconazole in that setting Although Ckrusei is intrinsically resistant to fluconazole it is rarely reported asa cause of systemic infection outside neutropenic patients Thus Cglabrata is the only species which might now limit the use offluconazole for the first line therapy of yeast fungaemia whenthe species is not identified Similarly patients who recentlyreceived fluconazole as antifungal prophylaxis should not be trea-ted with fluconazole for the curative treatment of a presumed orproven episode of systemic candidiasis The fungistatic effect offluconazole against Candida spp does not appear to influence theoutcome of candidaemic episodes at least in comparison withamphotericin B which is apparently fungicidal against Candidaspp Finally when summarizing its valuable properties the strongdemonstration of its efficacy in large randomized controlled trialsand selected clinical series its availability in various commercialpresentations and its current low cost fluconazole still remains aleading antifungal drug against susceptible Candida species

Transparency declarations

C C E H A L P R and F D have no conflicts to declareD W D In the past 5 years D W D has received grant supportfrom Astellas Merck Pfizer F2G OrthoBiotech Indevus Basileathe Fungal Research Trust the Wellcome Trust the National Insti-tute of Allergy and Infectious Diseases and the European Union Hehas been an advisorconsultant to Merck Basilea Vicuron (nowPfizer) Schering Plough Indevus F2G Nektar Daiichi SigmaTau Astellas PPL Therapeutics and Uriach He has been paid fortalks on behalf of Astellas Merck and Pfizer He holds foundershares in F2G Ltd and GBE Diagnostics Ltd and talks on behalf ofAstellas Merck and Gilead Sciences O L Speakers bureau forPfizer

References

1 Richardson K The discovery and profile of fluconazole J Chemo-

ther 1990 2 51ndash4

2 Richardson K Brammer KW Marriott MS et al Activity of

UK-49858 a bis-triazole derivative against experimental infections

with Candida albicans and Trichophyton mentagrophytes Antimicrob

Agents Chemother 1985 27 832ndash5

3 Vanrsquot Wout JW Mattie H van Furth R A prospective study of the

efficacyof fluconazole (UK-49858)againstdeep-seated fungal infections

J Antimicrob Chemother 1988 21 665ndash72Table

15

No

n-c

om

par

ativ

est

ud

ies

on

flu

con

azo

leas

cura

tiv

etr

eatm

ent

of

neo

nat

alca

nd

idae

mia

Ref

eren

ce

Nu

mb

ero

f

pat

ien

tsR

egim

enM

icro

bio

log

ical

cure

Sid

eef

fect

s

Dri

esse

net

al

22

02

1v

ery

low

bir

thw

eig

ht

5m

gk

gfo

r

1ndash

42

day

sm

ean

16

90

3

0

cyto

lyti

ch

epat

itis

Fas

anoet

al

21

54

05

mg

kg

for

2ndash

80

day

sm

ean

26

97

5

cy

toly

tic

hep

atit

is

Wai

ner

etal

21

61

91

0m

gk

go

nd

ay1

then

5m

gk

g

63

su

rviv

ing

32

fun

gal

free

dea

ths

NS

Hu

anget

al

21

71

8v

ery

low

bir

thw

eig

ht

3ndash

10

mg

kg

for

15

ndash1

73

day

sm

ean

34

6fi

rst

lin

etr

eatm

ent

83

13

afte

rA

MB

fail

ure

6

2

29

cy

toly

tic

hep

atit

is

Hu

tto

vaet

al

21

84

0v

ery

low

bir

thw

eig

ht

6m

gk

gfo

r6

ndash4

8d

ays

65

cu

rew

ith

ou

tre

lap

se5

cy

toly

tic

hep

atit

is

5

-ele

vat

edse

rum

crea

tin

ine

Gu

rpin

aret

al

21

92

42

ndash1

6m

gk

gfo

r

5ndash

72

day

sm

ean

25

96

8

an

aem

iao

rcy

toly

tic

hep

atit

is

Sch

war

zeet

al

11

53

5ndash

6m

gk

gfo

r3

wee

ks

mea

n2

17

8

4

cyto

lyti

ch

epat

itis

AM

B

amphote

rici

nB

ver

ylo

wbir

thw

eight

lt1500

g

NS

st

atis

tica

lly

not

signif

ican

t

Review

404

4 Vanrsquot Wout JW deGraeff-Meeder ER Paul LC et al Treatment of

two cases of cryptococcal meningitis with fluconazole Scand J Infect Dis

1988 20 193ndash8

5 Tucker RM Williams PL Arathoon EG et al Pharmacokinetics of

fluconazole in cerebrospinal fluid and serum in human coccidioidal

meningitis Antimicrob Agents Chemother 1988 32 369ndash73

6 ByrneWRWajszczukCPCryptococcalmeningitis in theacquired

immunodeficiency syndrome (AIDS) successful treatment with flucona-

zole after failure of amphotericin B Ann Intern Med 1988 108 384ndash5

7 HughesCE BeggsWH Action of fluconazole (UK-49858) in rela-

tion to other systemic antifungal azoles J Antimicrob Chemother 1987

19 171ndash4

8 DebruyneDClinicalpharmacokineticsof fluconazole insuperficial

and systemic mycoses Clin Pharmacokinet 1997 33 52ndash77

9 Brammer KW Coates PE Pharmacokinetics of fluconazole in

pediatric patients Eur J Clin Microbiol Infect Dis 1994 13 325ndash9

10 Schwarze R Penk A Pittrow L Administration of fluconazole in

children below 1 year of age Mycoses 1999 42 3ndash16

11 Schwarze R Penk A Pittrow L Treatment of candidal infections

with fluconazole in neonates and infants Eur J Med Res 2000 5 203ndash8

12 Thaler FBernardBTodMet al Fluconazolepenetration in cereb-

ral parenchyma in humans at steady stateAntimicrob Agents Chemother

1995 5 1154ndash6

13 Bozzette SA Gordon RL Yen A et al Biliary concentrations of

fluconazole in a patient with candidal cholecystitis case reportClin Infect

Dis 1992 4 701ndash3

14 Debruyne D Ryckelynck JP Moulin M et al Pharmacokinetics of

fluconazole in patients undergoing continuous ambulatory peritoneal dial-

ysis Clin Pharmacokinet 1990 18 491ndash8

15 Tod M Lortholary O Padoin C et al Intravenous penetration of

fluconazole during endophthalmitis Clin Microbiol Infect 1997 3 143ndash4

16 Urbak SF Degn T Fluconazole in the management of fungal ocu-

lar infections Ophthalmologica 1994 3 147ndash56

17 Fasano C OrsquoKeefe J Gibbs D Fluconazole treatment of children

with severe fungal infections not treatable with conventional agentsEur J

Clin Microbiol Infect Dis 1994 13 344ndash7

18 Aleck KA Bartley DL Multiple malformation syndrome following

fluconazole use in pregnancy report of an additional patient Am J Med

Genet 1997 72 253ndash6

19 Buijk SL Gyssens IC Mouton JW et al Pharmacokinetics of

sequential intravenous and enteral fluconazole in critically ill surgical

patients with invasive mycoses and compromised gastro-intestinal func-

tion Intensive Care Med 2001 27 115ndash21

20 El-Yazigi AEllisMErnstPet al Pharmacokinetics of oral flucona-

zole when used for prophylaxis in bone marrow transplant recipients

Antimicrob Agents Chemother 1997 41 914ndash17

21 Finch CK Green CA Self TH Fluconazole-carbamazepine inter-

action South Med J 2002 95 1099ndash100

22 Tucker RM Denning DW Hanson RH et al Interaction of azoles

with rifampin phenytoin and carbamazepine in vitro and clinical obser-

vations Clin Infect Dis 1992 14 165ndash74

23 Stockley IH Stockleyrsquos Drug Interactions A Source Book of Inter-

actions Their Mechanisms Clinical Importance and Management 6th

edn London UK Pharmaceutical Press 2002

24 von Moltke LL Greenblatt DJ Duan SX et al Inhibition of terfena-

dine metabolism in vitro by azole antifungal agents and by selective sero-

tonin reuptake inhibitor antidepressants relation to pharmacokinetic

interactions in vivo J Clin Psychopharmacol 1996 16 104ndash12

25 BrockmeyerNH Tillmann I Mertins L et al Pharmacokinetic inter-

action of fluconazole and zidovudine in HIV-positive patients Eur J Med

Res 1997 2 377ndash83

26 van Burik JA LeisenringW Myerson D et al The effect of prophy-

lactic fluconazole on the clinical spectrum of fungal diseases in bone

marrow transplant recipients with special attention to hepatic candidiasis

An autopsy study of 355 patients Medicine 1998 77 246ndash54

27 Wingard JR Antifungal chemoprophylaxis after blood andmarrow

transplantation Clin Infect Dis 2002 34 1386ndash90

28 GarbinoJLewDPRomandJAetalPreventionofsevereCandida

infections in nonneutropenic high-risk critically ill patients a randomized

double-blind placebo-controlled trial in patients treatedbyselectivediges-

tive decontamination Intensive Care Med 2002 28 1708ndash17

29 Gearhart MO Worsening of liver function with fluconazole and

review of azole antifungal hepatotoxicity Ann Pharmacother 1994 281177ndash81

30 Crerar-Gilbert A Boots R Fraenkel D et al Survival following ful-

minant hepatic failure from fluconazole induced hepatitis Anaesth Inten-

sive Care 1999 27 650ndash2

31 PappasPGKauffmanCAPerfect Jetal Alopeciaassociatedwith

fluconazole therapy Ann Intern Med 1995 123 354ndash7

32 Stevens DA Diaz M Negroni R et al Safety evaluation of chronic

fluconazole therapy Fluconazole Pan-American Study Group

Chemotherapy 1997 5 371ndash7

33 Anaissie EJ Kontoyiannis DP Huls C et al Safety plasma con-

centrations and efficacy of high-dose fluconazole in invasive mold infec-

tions J Infect Dis 1995 172 599ndash602

34 Gussenhoven MJ Haak A Peereboom-Wynia JD et al Stevens-

Johnson syndrome after fluconazole Lancet 1991 338 120

35 NovelliVHolzelHSafetyand tolerabilityof fluconazole inchildrenAntimicrob Agents Chemother 1999 43 1955ndash60

36 Koks CH Crommentuyn KM Hoetelmans RM et al Can

fluconazole concentrations in saliva be used for therapeutic drug mon-

itoring Ther Drug Monit 2001 4 449ndash53

37 Louie A Drusano GL Banerjee P et al Pharmacodynamics of

fluconazole in amurinemodel of systemic candidiasisAntimicrob Agents

Chemother 1998 42 1105ndash9

38 PittrowLPenkAPlasmaand tissueconcentrationsof fluconazole

and their correlation to breakpoints Mycoses 1997 40 25ndash32

39 Rex JH Pfaller MA Galgiani JN et al Development of interpretive

breakpoints forantifungalsusceptibility testing conceptual frameworkand

analysis of in vitro-in vivo correlation data for fluconazole itraconazole

and Candida infections Subcommittee on Antifungal Susceptibility Test-

ingof theNationalCommittee forClinical LaboratoryStandardsClin Infect

Dis 1997 24 235ndash47

40 Pfaller MA Diekema DJ Twelve years of fluconazole in clinical

practiceglobal trends inspeciesdistributionand fluconazolesusceptibility

of bloodstream isolatesofCandida International FungalSurveillancePar-

ticipant Group Clin Microbiol Infect 2004 10 Suppl 1 11ndash23

41 Tortorano AM Rigoni AL Biraghi E et al The European Confed-

eration of Medical Mycology (ECMM) survey of candidaemia in Italy anti-

fungal susceptibility patterns of 261 non-albicans Candida isolates from

blood J Antimicrob Chemother 2003 52 679ndash82

42 Pfaller MAMesser SA Boyken L et al Geographic variation in the

susceptibilities of invasive isolates of Candida glabrata to seven systemi-

cally active antifungal agents a global assessment from the ARTEMIS

Antifungal Surveillance Program conducted in 2001 and 2002 J Clin

Microbiol 2004 42 3142ndash6

43 Paya CV Fungal infections in solid-organ transplantation Clin

Infect Dis 1993 16 677ndash88

44 Singh N Wagener MM Marino IR et al Trends in invasive fungal

infections in liver transplant recipients correlation with evolution in trans-

plantation practices Transplantation 2002 73 63ndash7

45 Fung JJ Fungal infection in liver transplantation Transplant InfectDis 2002 4 18ndash23

46 Winston DJ Pakrasi A Busuttil RW Prophylactic fluconazole in

liver transplant recipientsA randomized double-blind placebo-controlled

trial Ann Intern Med 1999 131 729ndash37

47 Gladdy RA Richardson SE Davies HD et al Candida infection in

pediatric liver transplant recipients Liver Transpl Surg 1999 5 16ndash24

Review

405

48 Castaldo P Stratta RJ Wood RP et al Clinical spectrum of fungal

infections after orthotopic liver transplantation Arch Surg 1991 126149ndash56

49 Husain S Tollemar J Dominguez EA et al Changes in the spec-

trum and risk factors for invasive candidiasis in liver transplant recipients

prospective multicenter case-controlled study Transplantation 2003

75 2023ndash9

50 GeorgeMJ Snydman DRWerner BG et al The independent role

of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic

liver transplant recipients Boston Center for Liver Transplantation

CMVIG-Study Group Cytogam MedImmune Inc Gaithersburg Mary-

land Am J Med 1997 103 106ndash13

51 Dockrell DH Mendez JC Jones M et al Human herpesvirus 6

seronegativity before transplantation predicts the occurrence of fungal

infection in liver transplant recipientsTransplantation 1999 67 399ndash403

52 Tollemar J Ericzon BG Barkholt L et al Risk factors for deep

Candida infections in liver transplant recipients Transplant Proc 1990

22 1826ndash7

53 Lumbreras C Cuervas-Mons V Jara P et al Randomized trial of

fluconazole versus nystatin for the prophylaxis of Candida infection

following liver transplantation J Infect Dis 1996 174 583ndash8

54 Winston DJ Busuttil RW Randomized controlled trial of oral itra-

conazole solution versus intravenousoral fluconazole for prevention of

fungal infections in liver transplant recipients Transplantation 2002

74 688ndash95

55 Tortorano AM Viviani MA PaganoA et al Candida colonization in

orthotopic liver tranplantation fuconazole versus oral amphoericin B

J Mycol Med 1995 5 21ndash4

56 Kung N Fisher N Gunson B et al Fluconazole prophylaxis for

high-risk liver transplant recipients Lancet 1995 345 1234ndash5

57 Pappas PG Rex JH Sobel JD et al Guidelines for treatment of

candidiasis Clin Infect Dis 2004 38 161ndash89

58 PayaCV Prevention of fungal infection in transplantation TransplInfect Dis 2002 4 S46ndash51

59 LortholaryO Dupont B Antifungal prophylaxis during neutropenia

and immunodeficiency Clin Microbiol Rev 1997 10 477ndash504

60 Benedetti E Gruessner AC Troppmann C et al Intra-abdominal

fungal infections after pancreatic transplantation incidence treatment

and outcome J Am Coll Surg 1996 183 307ndash16

61 LumbrerasC Fernandez I Velosa J et al Infectious complications

following pancreatic transplantation incidence microbiological and clini-

cal characteristics and outcome Clin Infect Dis 1995 20 514ndash20

62 Patterson JE Epidemiology of fungal infections in solid organ

transplant patients Transpl Infect Dis 1999 1 229ndash36

63 Kusne S Furukawa H Abu-Elmagd K et al Infectious complica-

tions after small bowel transplantation in adults an update Transplant

Proc 1996 28 2761ndash2

64 Paterson DL Ndirangu M Kwak EJ et al Opportunistic infections

in solid-organ transplant recipients pre-treated with alumetuzumab In

Abstracts of the Forty-Fourth Interscience Conference on Antimicrobial

Agents and Chemotherapy Washington DC 2004 Abstract K-1427 p

357 American Society for Microbiology Washington DC USA

65 Kramer MR Marshall SE Starnes VA et al Infectious complica-

tions in heart-lung transplantation Analysis of 200 episodes Arch Intern

Med 1993 153 2010ndash6

66 Goodrich JMReedECMori M et al Clinical features and analysis

of risk factors for invasive candidal infection after marrow transplantation

J Infect Dis 1991 164 731ndash40

67 Dykewicz CA Centers for Disease Control and Prevention (US)

Infectious Diseases Society of America American Society of Blood and

MarrowTransplantation Summary of the guidelines for preventing oppor-

tunistic infections among hematopoietic stem cell transplant recipients

Clin Infect Dis 2001 33 139ndash44

68 Sable CA Donowitz GR Infections in bone marrow transplant

recipients Clin Infect Dis 1994 18 273ndash81

69 Goodman JLWinston DJ Greenfield RA et al A controlled trial of

fluconazole to prevent fungal infections in patients undergoing bone mar-

row transplantation N Engl J Med 1992 326 845ndash51

70 Slavin MA Osborne B Adams R et al Efficacy and safety of flu-

conazole prophylaxis for fungal infectionsaftermarrow transplantationmdasha

prospective randomized double-blind study J Infect Dis 1995 1711545ndash52

71 Marr KA Seidel K SlavinMA et al Prolonged fluconazole prophy-

laxis is associated with persistent protection against candidiasis-related

death in allogeneic marrow transplant recipients long-term follow-up of a

randomized placebo-controlled trial Blood 2000 96 2055ndash61

72 AlangadenGChandrasekar PH BaileyE et al Antifungal prophy-

laxis with low-dose fluconazole during bone marrow transplantation The

Bone Marrow Transplantation Team Bone Marrow Transplant 1994 14919ndash24

73 Wolff SN Fay J Stevens D et al Fluconazole versus low-dose

amphotericin B for the prevention of fungal infections in patients under-

going bonemarrow transplantation a study of theNorthAmericanMarrow

Transplant Group Bone Marrow Transplant 2000 25 853ndash9

74 Annaloro C Oriana A Tagliaferri E et al Efficacy of different pro-

phylactic antifungal regimens in bone marrow transplantation Haemato-

logica 1995 80 512ndash17

75 Winston DJ Maziarz RT Chandrasekar PH et al Intravenous and

oral itraconazole versus intravenous and oral fluconazole for long-term

antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant

recipients A multicenter randomized trial Ann Intern Med 2003 138705ndash13

76 MarrKACrippaF LeisenringWet al Itraconazoleversus flucona-

zole forpreventionof fungal infections inpatients receivingallogeneicstem

cell transplants Blood 2004 103 1527ndash33

77 MacMillan ML Goodman JL DeFor TE et al Fluconazole to pre-

vent yeast infections in bone marrow transplantation patients a random-

ized trial of high versus reduced dose and determination of the value of

maintenance therapy Am J Med 2002 112 369ndash79

78 Marr KA Seidel K White TC et al Candidemia in allogeneic blood

and marrow transplant recipients evolution of risk factors after the adop-

tion of prophylactic fluconazole J Infect Dis 2000 181 309ndash16

79 van Burik JA Ratanatharathorn V Stepan DE et al Micafungin

versus fluconazole for prophylaxis against invasive fungal infections dur-

ing neutropenia in patients undergoing hematopoietic stem cell trans-

plantation Clin Infect Dis 2004 39 1407ndash16

80 Prentice HG Kibbler CC Prentice AG Towards a targeted risk-

based antifungal strategy in neutropenic patients Br J Haematol 2000

110 273ndash84

81 Laverdiere M Rotstein C Bow EJ et al Impact of fluconazole

prophylaxis on fungal colonizatin and infection rates in neutropenic

patients The Canadian Fluconazole Study J Animicrob Chemother

2000 46 1001ndash8

82 Winston DJ Chandrasekar PH Lazarus HM et al Fluconazole

prophylaxis of fungal infections in patients with acute leukemia Results

of a randomized placebo-controlled double-blind multicenter trial Ann

Intern Med 1993 118 495ndash503

83 Chandrasekar PHGatnyCMEffect of fluconazole prophylaxis on

fever and use of amphotericin in neutropenic cancer patients Bone Mar-

row Transplantation Team Chemotherapy 1994 40 136ndash43

84 Rotstein C Bow EJ Laverdiere M et al Randomized placebo-

controlled trial of fluconazole prophylaxis for neutropenic cancer patients

benefit basedonpurposeand intensity of cytotoxic therapy TheCanadian

Fluconazole Prophylaxis Study Group Clin Infect Dis 1999 28 331ndash40

85 YamacK Senol E HaznedarR Prophylactic use of fluconazole in

neutropenic cancer patients Postgrad Med J 1997 71 284ndash6

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to reducemortality or the requirement of systemic amphotericin B therapy

during treatment for refractory acute myeloid leukemia results of a

Review

406

prospective randomized phase III study German AML Cooperative

Group Cancer 1998 83 291ndash301

87 SchaffnerA SchaffnerM Effect of prophylactic fluconazole on the

frequencyof fungal infectionsamphotericinBuseandhealthcarecosts in

patients undergoing intensive chemotherapy for hematologic neoplasias

J Infect Dis 1995 172 1035ndash41

88 Egger T Gratwohl A Tichelli A et al Comparison of fluconazole

with oral polyenes in the prevention of fungal infections in neutropenic

patients A prospective randomized single-center study Support Care

Cancer 1995 3 139ndash46

89 Morgenstern GR Prentice AG Prentice H et al A randomized

controlled trial of itraconazole versus fluconazole for the prevention of

fungal infections in patients with haematological malignancies UK Mul-

ticentre Antifungal Prophylaxis Study Group Br J Haematol 1999 105901ndash11

90 EllisMEClinkHErnstPetalControlledstudyof fluconazole in the

preventionof fungal infections in neutropenic patientswith haematological

malignancies and bone marrow transplant recipients Eur J Clin Microbiol

Infect Dis 1994 13 3ndash11

91 Philpott-Howard JN Wade JJ Mufti GJ et al Randomized com-

parisonoforal fluconazoleversusoralpolyenes for thepreventionof fungal

infection in patients at risk of neutropenia Multicentre Study Group

J Antimicrob Chemother 1993 31 973ndash84

92 Ninane J A multicentre study of fluconazole versus oral polyenes

in the prevention of fungal infection in children with hematological or

oncological malignancies Multicentre Study Group Eur J Clin Microbiol

Infect Dis 1994 13 330ndash7

93 Menichetti F Del Favero A Martino P et al Preventing fungal

infection in neutropenic patients with acute leukemia fluconazole com-

pared with oral amphotericin B The GIMEMA Infection Program Ann

Intern Med 1994 120 913ndash18

94 Akiyama H Mori S Tanikawa S et al Fluconazole versus oral

amphotericin B in preventing fungal infection in chemotherapy-induced

neutropenic patients with haematological malignancies Mycoses 1996

36 373ndash8

95 Meunier F AounM JanssensM et al Chemoprophylaxis of fungal

infections in granulocytopenic patients using fluconazole versus oral

amphotericin B Drug Invest 1991 3 258ndash65

96 Rozenberg-Arska M Dekker AW Branger J et al A randomized

study to compare oral fluconazole to amphotericin B in the prevention of

fungal infections inpatientswithacute leukaemiaJAntimicrobChemother

1991 27 369ndash76

97 Brammer KW Management of fungal infection in neutropenic

patients with fluconazole Haematol Blood Transfus 1990 33 546ndash50

98 Bodey GP Anaissie EJ Elting LS et al Antifungal prophylaxis

during remission induction therapy for acute leukemia fluconazole versus

intravenous amphotericin B Cancer 1994 73 2099ndash106

99 Kanda Y Yamamoto R Chizuka A et al Prophylactic action of

oral fluconazole against fungal infection in neutropenic patients A

meta-analysis of 16 randomized controlled trials Cancer 2000 891611ndash25

100 Bow EJ Laverdiere M Lussier N et al Antifungal prophylaxis for

severely neutropenic chemotherapy recipients a meta analysis of

randomized-controlled clinical trials Cancer 2002 94 3230ndash46

101 Viscoli C Paesmans M Sanz M et al Association between

antifungal prophylaxis and rate of documented bacteremia in febrile

neutropenic cancer patients Clin Infect Dis 2001 32 1532ndash7

102 HughesWT Armstrong D BodeyGP et al 2002 guidelines for the

use of antimicrobial agents in neutropenic patients with cancerClin Infect

Dis 2002 34 730ndash51

103 Cornely OA Bohme A Buchheidt D et al Prophylaxis of invasive

fungal infections in patients with hematological malignancies and solid

tumorsmdashguidelines of the Infectious Diseases Working Party (AGIHO)

of the German Society of Hematology and Oncology (DGHO) Ann

Hematol 2003 82 Suppl 2 186ndash200

104 McNeil MM Nash SL Hajjeh RA et al Trends in mortality due to

invasivemycotic diseases in theUnitedStates 1980ndash1997Clin InfectDis

2001 33 641ndash7

105 KibblerCCSeatonSBarnesRA et alManagement and outcome

of bloodstream infections due to Candida species in England and Wales

J Hosp Infect 2003 54 18ndash24

106 Marchetti O Bille J Fluckiger U et al Fungal Infection Network of

Switzerland Epidemiology of candidemia in Swiss tertiary care hospitals

secular trends 1991-2000 Clin Infect Dis 2004 38 311ndash20

107 Gudlaugsson O Gillespie S Lee K et al Attributable mortality of

nosocomial candidemia revisited Clin Infect Dis 2003 37 1172ndash7

108 Ibanez-Nolla J Nolla-Salas M Leon MA et al Early diagnosis of

candidiasis in nonneutropenic critically ill patients J Infect 2004 48181ndash92

109 BlumbergHMJarvisWRSoucieJMetalRisk factors for candidal

bloodstream infections in surgical intensive care unit patients the NEMIS

prospective multicenter study The National Epidemiology of Mycosis

Survey Clin Infect Dis 2001 33 177ndash86

110 Pittet D Monod M Suter PM et al Candida colonization and

subsequent infections in critically ill surgical patients Ann Surg 1994

220 751ndash8

111 Sendid B Poirot JL Tabouret M et al Combined detection of

mannanaemia and antimannan antibodies as a strategy for the diagnosis

of systemic infectioncausedbypathogenicCandidaspeciesJMedMicro-

biol 2002 51 433ndash42

112 Bar W Hecker H Diagnosis of systemic Candida infections in

patients of the intensive care unit Significance of serum antigens and

antibodies Mycoses 2002 45 22ndash8

113 Calandra T Marchetti O Clinical trials of antifungal prophy-

laxis among patients undergoing surgery Clin Infect Dis 2004 39S185ndash92

114 Sypula WT Kale-Pradhan PB Therapeutic dilemma of flucona-

zole prophylaxis in intensive care Ann Pharmacother 2002 36 155ndash9

115 Pelz RK Hendrix CW Swoboda SM et al Double-blind placebo-

controlled trial of fluconazole to prevent candidal infections in critically ill

surgical patients Ann Surg 2001 233 542ndash8

116 Eggimann P Francioli P Bille J et al Fluconazole prophylaxis

prevents intraabdominal candidiasis in high-risk surgical patients Crit

Care Med 1997 27 1066ndash72

117 Swoboda SM Merz WG Lipsetta PA Candidemia the impact of

antifungal prophylaxis in a surgical intensive care unitSurg Infect20034345ndash54

118 Todd JC OrsquoNeal VG Grady KP et al Reduction of secondary

mycotic infections in the trauma intensivie care unit with fluconazole

J Trauma 1991 31 1722ndash27

119 Jacobs S Price Evans DA Tariq M et al Fluconazole improves

survival in septic shock a randomized double-blind prospective studyCrit

Care Med 2003 31 1938ndash46

120 Zervos EE Fink GW Norman JG et al Fluconazole increases

bactericidal activity of neutrophils through non-cytokine-mediated path-

way J Trauma 1996 41 465ndash70

121 AblesAZBlumerNAValainisGTetal Fluconazoleprophylaxis of

severe Candida infection in trauma and postsurgical patients a prospec-

tive double-blind randomised placebo-controlled trial Infect Dis Clin

Pract 2000 9 169ndash75

122 Kam LW Lin JD Management of systemic candidal infections in

the intensive care unit Am J Health Syst Pharm 2002 59 33ndash41

123 Rocco TR Reinert SE Simms HH Effects of fluconazole admin-

istration in critically ill patients analysis of bacterial and fungal resistance

Arch Surg 2000 135 160ndash5

124 Tortorano AM Caspani L Rigoni AL et al Candidosis in the inten-

sive care unit a 20-year survey J Hosp Infect 2004 57 8ndash13

125 EggimannPGarbino J Pittet DManagement ofCandida species

infections in critically ill patients Lancet Infect Dis 2003 3 772ndash85

Review

407

126 EggimannPGarbinoJPittetDEpidemiologyofCandida species

infections incritically ill non-immunosuppressedpatientsLancet InfectDis

2003 3 685ndash702

127 Martins MD Lozano-Chiu M Rex JH Declining rates of oropha-

ryngeal candidiasis and carriage of Candida albicans associated with

trends toward reduced rates of carriage of fluconazole-resistant C albi-

cans in human immunodeficiency virus-infected patients Clin Infect Dis

1998 27 1291ndash4

128 Powderly WG Finkelstein D Feinberg J et al A randomized trial

comparing fluconazole with clotrimazole troches for the prevention of fun-

gal infections in patients with advanced human immunodeficiency virus

infection NIAID AIDS Clinical Trials Group N Engl J Med 1995 332700ndash5

129 Leen CL Dunbar EM Ellis ME et al Once-weekly fluconazole to

prevent recurrenceof oropharyngeal candidiasis inpatientswithAIDSand

AIDS-related complex a double-blind placebo-controlled study J Infect

1990 21 55ndash60

130 Stevens DA Greene SI Lang OS Thrush can be prevented in

patients with acquired immunodeficiency syndrome and the acquired

immunodeficiency syndrome-related complex Randomized double-

blind placebo-controlled study of 100-mg oral fluconazole daily Arch

Intern Med 1991 151 2458ndash64

131 Just-Nubling G Gentschew G Meissner K Fluconazole prophy-

laxis of recurrent oral candidiasis inHIV-positive patientsEur JClinMicro-

biol Infect Dis 1991 10 917ndash21

132 Marriott DJ Jones PD Hoy JF et al Fluconazole once a week as

secondary prophylaxis against oropharyngeal candidiasis in HIV-infected

patients A double-blind placebo-controlled studyMed J Aust 1993 158312ndash16

133 Schuman P Capps L Peng G et al Weekly fluconazole for the

prevention ofmucosal candidiasis inwomenwithHIV infection A random-

ized double-blind placebo-controlled trial Terry Beirn Community Pro-

grams for Clinical Research on AIDSAnn InternMed 1997 126 689ndash96

134 Havlir DV DubeMPMcCutchan JA et al Prophylaxis with weekly

versus daily fluconazole for fungal infections in patients with AIDS Clin

Infect Dis 1998 27 1369ndash75

135 Pagani JL Chave JP Casjka C et al Efficacy tolerability and

development of resistance in HIV-positive patients treated with flucona-

zole for secondary prevention of oropharyngeal candidiasis a random-

ized double-blind placebo-controlled trial JAntimicrobChemother 2002

50 231ndash40

136 Vazquez JA Peng G Sobel JD et al Evolution of antifungal sus-

ceptibility amongCandidaspecies isolates recovered fromhuman immun-

odeficiency virus-infected women receiving fluconazole prophylaxis Clin

Infect Dis 2001 33 1069ndash75

137 Delfraissy JF Prise en charge therapeutique des patients infectespas le VIH Rapport Delfraissy Paris Flammarion 2004

138 DePauwBERaemaekers JMDonnelly JPet al Anopenstudyon

the safety and efficacy of fluconazole in the treatment of disseminated

Candida infections in patients treated for hematological malignancy Ann

Hematol 1995 70 83ndash7

139 Anaissie EJ Vartivarian SE Abi-Said D et al Fluconazole versus

amphotericin B in the treatment of hematogenous candidiasis a matched

cohort study Am J Med 1996 101 170ndash6

140 Anaissie EJ Darouiche RO Abi-Said D et al Management of

invasive candidal infections results of a prospective randomized multi-

center study of fluconazole versus amphotericin B and review of the

literature Clin Infect Dis 1996 23 964ndash72

141 Myoken Y Kyo T Kohara T et al Breakthrough fungemia caused

by azole-resistant Candida albicans in neutropenic patients with acute

leukemia Clin Infect Dis 2003 36 1496ndash7

142 Anttila VJ FarkkilaM JanssonSE et al Diagnostic laparoscopy in

patientswith acute leukemiaandsuspectedhepatic candidiasisEur JClin

Microbiol Infect Dis 1997 16 637ndash43

143 Anaissie E Bodey GP Kantarjian H et al Fluconazole therapy for

chronic disseminated candidiasis in patients with leukemia and prior

amphotericin B therapy Am J Med 1991 91 142ndash50

144 KauffmanCA BradleySFRossSC et al Hepatosplenic candidia-

sis successful treatment with fluconazole Am J Med 1991 91 137ndash41

145 Kontoyiannis DP Luna MA Samuels BI et al Hepatosplenic can-

didiasis A manifestation of chronic disseminated candidiasis Infect Dis

Clin North Am 2000 14 721ndash39

146 Graninger W Presteril E Schneeweiss B et al Treatment of

Candida albicans fungaemia with fluconazole J Infect 1993 26 133ndash46

147 Phillips P Shafran S Garber G et al Multicenter randomized trial

of fluconazole versus amphotericin B for treatment of candidemia in

non-neutropenic patients Canadian Candidemia Study Group Eur J

Clin Microbiol Infect Dis 1997 16 337ndash45

148 Rex JH Bennett JE Sugar AM et alA randomized trial comparing

fluconazolewithamphotericinB for the treatmentof candidemia inpatients

without neutropenia Candidemia Study Group and the National Institute

N Engl J Med 1994 331 1325ndash30

149 Abele-Horn M Kopp A Sternberg U et al A randomized study

comparing fluconazolewith amphotericinB5-flucytosine for the treatment

of systemic Candida infections in intensive care patients Infection 1996

24 426ndash32

150 Nguyen MH Peacock JE Jr Tanner DC et al Therapeutic

approaches in patients with candidemia Evaluation in a multicenter

prospective observational study Arch Intern Med 1995 155 2429ndash35

151 Rex JH Pappas PG Karchmer AW et al A randomized and

blinded multicenter trial of high-dose fluconazole plus placebo versus flu-

conazole plus amphotericin B as therapy for candidemia and its con-

sequences in non-neutropenic subjectsClin Infect Dis 2003 36 1221ndash8

152 Mora-Duarte J Betts R Rotstein C et al Comparison of

caspofungin and amphotericin B for invasive candidiasis N Engl J Med

2002 347 2020ndash9

153 Sugar AM Saunders C Diamond RD et al Successful treatment

of Candida osteomyelitis with fluconazole A noncomparative study of

two patients Diagn Microbiol Infect Dis 1990 13 517ndash20

154 Tang C Successful treatment of Candida albicans osteomyelitis

with fluconazole J Infect 1993 26 89ndash92

155 LafontAOliveAGelmanMet alCandidaalbicansspondylodisci-

tis and vertebral osteomyelitis in patients with intravenous heroin drug

addiction Report of 3 new cases J Rheumatol 1994 21 953ndash6

156 Hennequin C Bouree P Hiesse C et al Spondylodiskitis due to

Candida albicans report of two patients who were successfully treated

with fluconazole and review of the literature Clin Infect Dis 1996 23176ndash8

157 Jonnalagadda S VeerabaguMP Rakela J et alCandida albicans

osteomyelitis in a liver transplant recipient a case report and review of the

literature Transplantation 1996 62 1182ndash4

158 Rossel P Schonheyder HC Nielsen H Fluconazole therapy

inCandidaalbicansspondylodiscitisScandJ InfectDis199830 527ndash30

159 TurnerDLJohnsonSARuleSASuccessful treatmentof candidal

osteomyelitis with fluconazole following failure with liposomal ampho-

tericin B J Infect 1999 38 51ndash3

160 El-Zaatari MM Hulten K Fares Y et al Successful treatment of

Candida albicans osteomyelitis of the spine with fluconazole and surgical

debridement case report J Chemother 2002 14 627ndash30

161 Seravalli L Van Linthoudt D Bernet C et al Candida glabrata

spinal osteomyelitis involving two contiguous lumbar vertebrae a case

report and review of the literature Diagn Microbiol Infect Dis 2003 45137ndash41

162 Garbino J Schnyder I LewDP et al An unusual cause of vertebral

osteomyelitis Candida species Scand J Infect Dis 2003 35 288ndash91

163 TunkelARThomasCYWispelweyBCandidaprostheticarthritis

report of a case treated with fluconazole and review of the literature Am J

Med 1993 94 100ndash3

Review

408

164 CushingRD FulgenziWR Synovial fluid levels of fluconazole in a

patient with Candida parapsilosis prosthetic joint infection who had an

excellent clinical response J Arthroplasty 1997 12 950

165 Fukasawa N Shirakura K Candida arthritis after total knee

arthroplastymdasha case of successful treatment without prosthesis removal

Acta Orthop Scand 1997 68 306ndash7

166 Lerch K Kalteis T Schubert T et al Prosthetic joint infections with

osteomyelitis due to Candida albicans Mycoses 2003 46 462ndash6

167 Clancy CJ Nguyen MH Morris AJ Candidal mediastinitis an

emerging clinical entity Clin Infect Dis 1997 25 608ndash13

168 PetrikkosGSkiadaA SabatakouH et al Case report Successful

treatment of two cases of post-surgical sternal osteomyelitis due to

Candida krusei and Candida albicans respectively with high doses of

triazoles (fluconazole itraconazole) Mycoses 2001 44 422ndash5

169 Weers-Pothoff GHavermans JF Kamphuis J et alCandida tropi-

calis arthritis in a patient with acutemyeloid leukemia successfully treated

with fluconazole case report and review of the literature Infection 1997

25 109ndash11

170 Laatikainen L TuominenM vonDickhoff K Treatment of endoge-

nous fungal endophthalmitis with systemic fluconazole with or without

vitrectomy Am J Ophthalmol 1992 113 205ndash7

171 Borne MJ Elliott JH OrsquoDay DM Ocular fluconazole treatment of

Candidaparapsilosisendophthalmitis after failed intravitreal amphotericin

B Arch Ophthalmol 1993 111 1326ndash7

172 Zarbin MA Becker E Witcher J et al Treatment of presumed

fungal endophthalmitis with oral fluconazole Ophthalmic Surg Lasers

1996 27 628ndash31

173 WongVK TasmanWEagleRC et al BilateralCandida parapsilo-

sis endophthalmitis Arch Ophthalmol 1997 115 670ndash2

174 Kauffman CA Bradley SF Vine AK Candida endophthalmitis

associated with intraocular lens implantation efficacy of fluconazole ther-

apy Mycoses 1993 36 13ndash17

175 del Palacio A Cuetara MS Ferro M et al Fluconazole in the man-

agement of endophthalmitis in disseminated candidosis of heroin addicts

Mycoses 1993 36 193ndash9

176 Luttrull JK Wan WL Kubak BM et al Treatment of ocular fungal

infections with oral fluconazole Am J Ophthalmol 1995 119 477ndash81

177 Akler ME Vellend H McNeely DM et al Use of fluconazole in the

treatment of candidal endophthalmitis Clin Infect Dis 1995 20 657ndash64

178 Christmas NJ Smiddy WE Vitrectomy and systemic fluconazole

for treatment of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1996 27 1012ndash18

179 EssmanTFFlynnHWSmiddyWEet al Treatment outcomes in a

10-year study of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1997 28 185ndash94

180 Martinez-Vazquez C Fernandez-Ulloa J Bordon J et al Candida

albicans endophthalmitis in brown heroin addicts response to early vit-

rectomyprecededand followedbyantifungal therapyClin InfectDis1998

27 1130ndash3

181 Aleixo MJ Caldeira L Ferreira ML Candida albicans meningitis

clinical case J Infect 2000 40 191ndash2

182 InoueY YozuR Ueda T et al A case report ofCandida parapsilo-

sis endocarditis J Heart Valve Dis 1998 7 240ndash2

183 Isalska BJ Stanbridge TN Fluconazole in the treatment of candi-

dal prosthetic valve endocarditis BMJ 1988 297 178ndash9

184 Martino P Meloni G Cassone A Candidal endocarditis and treat-

ment with fluconazole and granulocyte-macrophage colony-stimulating

factor Ann Intern Med 1990 112 966ndash7

185 Roupie E Darmon JY Brochard L et al Fluconazole therapy of

candidal native valveendocarditisEur JClinMicrobiol InfectDis199110458ndash9

186 Hernandez JA Gonzalez-Moreno M Llibre JM et al Candidal

mitral endocarditis and long-term treatment with fluconazole in a patient

with human immunodeficiency virus infection Clin Infect Dis 1992 151062ndash3

187 Venditti MDeBernardis FMicozzi A et al Fluconazole treatment

of catheter-related right-sided endocarditis caused by Candida albicans

and associated with endophthalmitis and folliculitis Clin Infect Dis 1992

14 422ndash6

188 Wallbridge DR McCartney AC Richardson MD Fluconazole in

the treatment ofCandidaprosthetic valveendocarditisMycoses199336259ndash61

189 Otaki M Kitamura N Candida prosthetic valve endocarditis An

autopsy review Int Surg 1993 78 252ndash3

190 Czwerwiec FS Bilsker MS Kamerman ML et al Long-term sur-

vival after fluconazole therapy of candidal prosthetic valve endocarditis

Am J Med 1993 94 545ndash6

191 Thakur RK Skelcy KM Kahn RN et al Successful treatment of

Candida prosthetic valve endocarditis with a combination of fluconazole

and amphotericin B Crit Care Med 1994 22 712ndash14

192 Cancelas JA Lopez JCabezudoE et al Native valve endocarditis

due toCandida parapsilosis a late complication after bonemarrow trans-

plantation-related fungemia Bone Marrow Transplant 1994 13 333ndash4

193 Zahid MA Klotz SA Hinthorn DR Medical treatment of recurrent

candidemia in a patient with probable Candida parapsilosis prosthetic

valve endocarditis Chest 1994 105 1597ndash8

194 Wells CJ Leech G Lever AM et al Treatment of native valve

Candida endocarditis with fluconazole J Infect 1995 31 233ndash5

195 Gilbert HM Peters ED Lang SJ et al Successful treatment of

fungal prosthetic valve endocarditis case report and review Clin Infect

Dis 1996 22 348ndash54

196 Nguyen MH Nguyen ML Yu VL et al Candida prosthetic valve

endocarditis prospective study of six cases and review of the literature

Clin Infect Dis 1996 22 262ndash7

197 Lejko-Zupanc T Kozelj M A case of recurrent Candida parapsilo-

sis prosthetic valve endocarditis cure bymedical treatment alone J Infect

1997 35 81ndash2

198 Joly V BelmatougN Leperre A et al Pacemaker endocarditis due

to Candida albicans case report and review Clin Infect Dis 1997 251359ndash62

199 Rex JH Walsh T Sobel JD et al Practice guidelines for the treat-

mentof candidiasis InfectiousDiseasesSocietyofAmericaClin InfectDis

2000 30 662ndash78

200 Baddour LM Long-term suppressive therapy for Candida para-

psilosis-induced prosthetic valve endocarditis Mayo Clin Proc 1995

70 773ndash5

201 Melgar GR Nasser RM Gordon SM Fungal prosthetic valve

endocarditis in 16 patients An 11-year experience in a tertiary care hos-

pital Medicine 1997 76 94ndash103

202 Dupont H Paugam-Burtz C Muller-Serieys C et al Predictive

factors of mortality due to polymicrobial peritonitis with Candida isolation

in peritoneal fluid in critically ill patients Arch Surg 2002 137 1341ndash6

203 Lee SC FungCP ChenHY et alCandida peritonitis due to peptic

ulcer perforation incidence rate risk factors prognosis and susceptibility

to fluconazole and amphotericin B Diagn Microbiol Infect Dis 2002 4423ndash7

204 Levine J Bernard DB Idelson BA et al Fungal peritonitis compli-

cating continuous ambulatory peritoneal dialysis successful treatment

with fluconazole a new orally active antifungal agent Am J Med 1989

86 825ndash7

205 Michel C Courdavault L al Khayat R et al Fungal peritonitis in

patients on peritoneal dialysis Am J Nephrol 1994 14 113ndash20

206 WangAYYuAWLi PKet al Factors predicting outcomeof fungal

peritonitis in peritoneal dialysis analysis of a 9-year experience of fungal

peritonitis in a single center Am J Kidney Dis 2000 36 1183ndash92

207 Hawkins JL Baddour LM Candida lusitaniae infections in the era

of fluconazole availability Clin Infect Dis 2003 36 14ndash18

Review

409

208 KauffmanCAVazquezJASobel JDetal Prospectivemulticenter

surveillance study of funguria in hospitalized patients The National Insti-

tute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group

Clin Infect Dis 2000 30 14ndash18

209 Sobel JD Kauffman CA McKinsey D et al Candiduria a random-

ized double-blind study of treatment with fluconazole and placebo The

National Institute of Allergy and Infectious Diseases (NIAID) Mycoses

Study Group Clin Infect Dis 2000 30 19ndash24

210 LundstromTSobel JNosocomial candiduria a reviewClin Infect

Dis 2001 32 1602ndash7

211 Kaufman D Boyle R Hazen KC et al Fluconazole prophylaxis

against fungal colonization and infection in preterm infants N Engl J

Med 2001 345 1660ndash6

212 Kicklighter SD Springer SC Cox T et al Fluconazole for the pro-

phylaxis against candidal rectal colonization in the very low birth weight

infant Pediatrics 2001 107 293ndash8

213 McGuire W Clerihew L Austin N Prophylactic intravenous anti-

fungal agents to prevent mortality and morbidity in very low birth weight

infants Cochrane Database Syst Rev 2004 CD003850

214 Agarwal JBansalSMalikGKetal Trends inneonatal septicemia

emergence of non-albicans Candida Indian Pediatr 2004 41 712ndash15

215 FasanoCOrsquoKeefe JGibbsD Fluconazole treatment of neonates

and infants with severe fungal infections not treatable with conventional

agents Eur J Clin Microbiol Infect Dis 1994 13 351ndash4

216 Wainer S Cooper PA Gouws H et al Prospective study of flu-

conazole therapy in systemicneonatal fungal infectionPediatr InfectDis J

1997 16 763ndash7

217 Huang YC Lin TY Lien RI et al Fluconazole therapy in neonatal

candidemia Am J Perinatol 2000 17 411ndash15

218 Huttova M Hartmanova I Kralinsky K et al Candida fungemia in

neonates treated with fluconazole report of forty cases including eight

with meningitis Pediatr Infect Dis J 1998 17 1012ndash15

219 Gurpinar AN Balkan E Kilic N et al Fluconazole treatment of

neonates and infants with severe fungal infections J Int Med Res 1997

25 214ndash18

220 Driessen M Ellis JB Muwazi F et al The treatment of systemic

candidiasis in neonates with oral fluconazole Ann Trop Pediatr 1997 17263ndash71

221 Driessen M Ellis JB Cooper PA et al Fluconazole vs

amphotericin B for the treatment of neonatal fungal septicemia

a prospective randomized trial Pediatr Infect Dis J 1997 151107ndash12

222 Marr B Gross S Cunningham C et al Candidal sepsis and

meningitis in a very-low-birth-weight infant successfully treated with flu-

conazole and flucytosine Clin Infect Dis 1994 19 795ndash6

223 Oleinik EM Della-Latta P Rinaldi MG et al Candida lusitaniae

osteomyelitis in a premature infant Am J Perinatol 1993 10 313ndash15

224 Mondal RK Singhi SC Chakrabarti A Randomized comparison

between fluconazole and itraconazole for the treatment of candidemia in a

pediatric intensive care unit a preliminary study Pediatr Crit Care Med

2004 5 561ndash5

225 Viscoli C Castagnola E Fioredda F et al Fluconazole in the treat-

ment of candidiasis in immunocompromised children Antimicrob Agents

Chemother 1991 35 365ndash7

226 Decruyenaere J Colardyn F Vogelaers D et al Combined use of

fluconazole and selective digestive decontamination in the prevention of

fungal infection after adult liver transplantation Transplant Proc 1995 273515ndash16

227 Koh LP Kurup A Goh YT et al Randomized trial of fluconazole

versus low-dose amphotericin B in prophylaxis against fungal infections in

patients undergoing hematopoietic stem cell transplantationAmJHema-

tol 2002 71 260ndash7

228 Gluckman E Esperou-Bourdeau H Ribaud P et al Comparaison

entre le fluconazole et le ketoconazole pour la prophylaxie des infections

fongiques chez les patients traites par greffe de moelle allogenique Cah

Oncol 1993 2 167ndash9

Review

410

Table

11

Stu

die

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nfl

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naz

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ascu

rati

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trea

tmen

tam

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on

-neu

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atie

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Ref

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yd

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ind

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infe

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nR

egim

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Du

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tmen

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Nu

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tsE

val

uat

ion

item

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ffic

acy

Ph

illi

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al

14

7R

M

C

PC

can

did

aem

iaF

LC

40

0m

gd

ayiv

ver

sus

AM

B

06

mg

kg

day

iv

4ndash

8w

eek

s5

0

53

clin

ical

mic

robio

logic

al

6m

on

ths

surv

ival

FL

C5

7

AM

B6

2

An

aiss

ieet

al

14

0R

M

C

PC

inv

asiv

e

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did

iasi

s

FL

C4

00

mg

day

iv

ver

sus

AM

B

25

ndash5

0m

gd

ayiv

9d

ays

75

67

clin

ical

mic

robio

logic

alE

OT

FL

C66

AM

B6

4

An

aiss

ieet

al

13

9O

S

Cca

nd

idae

mia

FL

C2

00

ndash6

00

mg

day

ver

sus

AM

B

03

ndash1

2m

gk

gd

ay

13

day

s

10

day

s

45

45

clin

ical

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robio

logic

al

D0

D

5

EO

T

FL

C7

3

AM

B7

1

Ab

ele-

Ho

rnet

al

14

9R

S

Cin

vas

ive

can

did

iasi

s

FL

C2

00

mg

day

iv

ver

sus

AM

B1

ndash1

5m

gk

g

ever

yo

ther

day

+

5F

C3middot

25

gd

ay

14

day

s3

6

36

clin

ical

mic

robio

logic

alE

OT

FL

C64

AM

B+

5F

C6

3

Ng

uy

enet

al

15

0O

M

C

PC

can

did

aem

iaF

LC

10

0ndash

80

0m

gd

ay

ver

sus

AM

B

13

day

s6

7

22

7

dea

thE

OT

no

dif

fere

nce

inm

ort

alit

yat

D+

7D

+1

4

D+

21

Rex

etal

14

8R

D

B

MC

can

did

aem

iaF

LC

40

0m

gd

ayiv

ver

sus

AM

B

06

mg

kg

day

iv

4ndash

8w

eek

s1

03

10

3

clin

ical

mic

robio

logic

alW

12

FL

C70

AM

B7

9

Rr

and

om

ized

D

Bd

ou

ble

bli

nd

S

Bs

ing

leb

lin

dP

Cp

lace

bo

con

tro

lled

S

Cs

ing

lece

ntr

eM

Cm

ult

icen

tre

FL

Cf

luco

naz

ole

A

MB

am

ph

ote

rici

nB

5

FC

flu

cyto

sin

ep

oo

ral

Dd

ayW

wee

kE

OT

en

do

ftr

eatm

ent

iv

intr

aven

ou

s

Review

399

response or death could be found In 1996 Anaissie et al139 com-pared the same drugs in cancer patients with candidiasis andenrolled 90 patients Doses of both fluconazole and amphotericinwere highly variable (fluconazole 200ndash600 mgday amphotericinB 03ndash12 mgkgday) The two cohorts were well matched andresponse rates at day 5 for each cohort were similar overallresponse rates were slightly better for fluconazole and therewere significantly fewer toxic effects in the fluconazole group

A more recent comparison of fluconazole versus fluconazoleplus amphotericin B in non-neutropenic subjects compared 800mgday of fluconazole versus the same dose plus 07 mgkgdayof amphotericin B in a randomized blinded multicentre trial invol-ving 219 patients151 Success rates were slightly higher and therewas a faster clearance rate of candidaemia in the combination groupcompared with fluconazole alone This suggests that the two drugsare not antagonistic and may perhaps act synergistically

Although fluconazole may be the preferred agent in non-neu-tropenic patients because of its low toxicity the recent introductionof caspofungin challenges this place particularly as it has a broaderspectrum of action A randomized study comparing caspofunginversus amphotericin B for the treatment of candidaemia in bothneutropenic and non-neutropenic patients has been completed butthere is no direct comparison with fluconazole152 Results of aprospective randomized controlled multicentre trial comparinganidulafungin a new echinocandin and fluconazole in patientswith candidaemia should be available soon

Fluconazole for the treatment of specific Candida

organ infections

All randomized studies using fluconazole to date have been under-taken in oesophageal candidiasis or candidaemia none in Candidaorgan infection although some patients with invasive candidiasishave been included in the randomized studies Therefore the datapresented here come from non-comparative open-label studies

Osteoarticular infections due to Candida sp

Very few data are available on the efficacy of fluconazole as firstline therapy in osteoarticular infections due to Candida sp Someobservations associated with spondylodiscitis have been publishedand have been summarized in Table 12153ndash162 Fluconazole (200ndash400 mgday initially gt2 months) proved to be efficacious in threecases of knee infections due to C parapsilosis163ndash165 A prostheticjoint infection and osteomyelitis of the knee due toC albicanswerecured with high doses of 800 mgday of fluconazole for 2 months incombination with repeated surgical debridement after a 10 daycourse of fluconazole 400 mgday which seemed to be ineffi-cient166 Fluconazole (400ndash800 mgday for 6 months) was alsoeffective for the treatment ofC albicans post-surgical mediastinitisin two cases167168 Fluconazole (400 mgday for 7 months) suc-cessfully treated an old patient with acute myeloid leukaemia whopresented with C tropicalis arthritis of the knee169 The latestIDSA guidelines recommend surgical debridement and initialcourse of amphotericin B for 2ndash3 weeks followed by fluconazolefor a total duration of 6ndash12 months57

Endophthalmitis due to Candida sp

A combination of partial or complete vitrectomy intraocularamphotericin B and antifungal drugs is the usual therapeuticapproach to Candida sp eye infections Several documented T

able

12

Rep

ort

so

fp

atie

nts

wit

hsp

on

dy

lod

isci

tis

du

eto

Candida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Lo

cali

zati

on

of

infe

ctio

n

Candida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Do

seo

ffl

uco

naz

ole

(mg

day

)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y

(fo

llo

w-u

pd

ura

tio

n)

Gar

bin

oet

al

16

2lu

mb

arCalbicans

14

00

3m

on

ths

(rel

apse

)

then

6m

on

ths

ndashre

cov

ery

(16

mo

nth

s)

lum

bar

Ctropicalis

18

00

foll

ow

edb

yit

raco

naz

ole

reco

ver

y(4

mo

nth

s)

Ser

aval

liet

al

16

1lu

mb

arCglabrata

18

00

3w

eek

sre

pla

ced

by

AM

B(7

0d

ays)

then

lip

idco

mp

lex

(56

day

s)

fail

ure

wit

hfl

uco

naz

ole

then

reco

ver

y(1

6m

on

ths)

El-

Zaa

tariet

al

16

0d

ors

alCalbicans

14

00

3m

on

ths

ndashre

cov

ery

(1y

ear)

Tu

rner

etal

15

9d

ors

o-l

um

bar

Calbicans

12

00

(1m

on

th)

then

10

01

2m

on

ths

afte

rfa

ilu

reo

fA

MB

li

po

som

al

AM

Ban

d5

FC

(9w

eek

s)

reco

ver

y(3

yea

rs)

Ro

ssel

etal

15

8d

ors

alCalbicans

14

00

(14

day

s)th

en2

00

7m

on

ths

afte

rfa

ilu

reo

fA

MB

(21

day

s)re

cov

ery

(1y

ear)

Jon

nal

agad

daet

al

15

7d

ors

alCalbicans

12

00

6m

on

ths

AM

B(3

g)

+5

FC

reco

ver

y(8

mo

nth

s)

Hen

neq

uin

etal

15

6lu

mb

arCalbicans

14

00

6m

on

ths

ndashre

cov

ery

(47

mo

nth

s)

lum

bar

C

alb

ican

s1

20

06

mo

nth

sndash

reco

ver

y(1

7m

on

ths)

Laf

on

tet

al

15

5lu

mb

arCalbicans

14

00

4w

eek

sndash

reco

ver

y(1

8m

on

ths)

Tan

get

al

15

4d

ors

alCalbicans

12

00

1y

ear

ndashre

cov

ery

(16

mo

nth

s)

Su

gar

etal

15

3d

ors

alan

dlu

mb

arCtropicalis

11

00

ndash1

50

1y

ear

AM

B(3

80

mg

)re

cov

ery

(26

mo

nth

s)

AM

B

amphote

rici

nB

5F

C

flucy

tosi

ne

Review

400

clinical cases reported the efficacy of fluconazole alone or incombination with other treatments in cases of endophthalmitisdue to Candida spp16170ndash173 Finally several recent series con-firmed fluconazole efficacy in cases of severe ocular infectionsdue to susceptible Candida sp in non-neutropenic patients174ndash180

Their results are summarized in Table 13 Most cases are due toC albicans and fluconazole-resistant species causing endoph-thalmitis is extremely rare On the basis of these data the IDSArecommends the use of fluconazole in this indication particularlyas follow-up therapy58

Meningitis due to Candida sp

Very few data exist on fluconazolersquos efficacy for the initial treat-ment of Candida sp meningitis in adults although this drug has avery good CSF penetration Oral fluconazole (800 mgday for3 months then 200 mgday) was successful for the treatment ofa C albicans meningitis in an HIV-infected patient with a CD4 cellcount of 35 cellsmm3 who refused intravenous therapy181

Endocarditis due to Candida sp

No series has documented the efficacy of fluconazole in endocard-itis due to Candida sp Only a few clinical cases have been pub-lished and most of these are summarized in Table 14182ndash198 Thesecases illustrate the efficacy of fluconazole (sometimes with nosurgical treatment) in endocarditis due to C albicans and alsoin endocarditis related to some non-albicans Candida spp espe-cially C parapsilosis However no study has demonstrated thesuperiority of fluconazole over amphotericin B in this indicationand there are insufficient data to recommend fluconazole as the firstline treatment for endocarditis due to Candida spp58199 Theechinocandins might have a place as primary therapy in thesecases Fluconazole (200ndash400 mgday) is often employed as partof a long-term suppressive regimen especially if valve replacementis not possible because of the high propensity for delayed relapse ofcandidal endocarditis200201

Peritonitis due to Candida sp

Peritonitis due to Candida sp may develop in patients with peri-toneal dialysis catheters or in those with surgical or traumaticinjury to the gut wall In this latter situation Candida spp areusually part of a polymicrobial infection Isolation of Candidaby direct examination of peritoneal fluid is an independent factorfor a severe outcome202 and recent small studies suggest thatprompt effective adequate and safe antifungal therapy shouldbe given in all cases of Candida sp peritonitis in order to lowerthe mortality rate and shorten the hospital stay113116 In a recentstudy of 23 cases secondary to peptic ulcer perforation the mor-tality rate in patients receiving fluconazole (200 mg intravenouslytwice daily for 2ndash4 weeks) was high (five of eight cases) probablyrelated to inadequate or too late initiation of antifungal therapy203

Some cases showing fluconazole efficacy have been reported inpatients with continuous ambulatory peritoneal dialysis eitheralone or in combination with flucytosine204ndash207 Catheter removalis crucial in these cases

Urinary infections due to Candida spp

Candida is by far the most frequent agent of urinary fungal infec-tions The line between colonization and real infection is generallyblurred Candiduria usually present as nosocomial infections T

able

13

Rep

ort

so

fp

atie

nts

wit

hen

do

ph

thal

mit

isd

ue

toCandida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Met

ho

do

log

y

of

stu

dy

Candida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Do

seo

f

flu

con

azo

le(m

gd

ay)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y

(fo

llo

w-u

pd

ura

tio

n)

Mar

tin

ez-V

azq

uez

etal

18

0p

rosp

ecti

ve

Calbicans

11

40

02

ndash8

wee

ks

AM

Biv

(n=

9)

or

no

trea

tmen

t(n

=1

)u

nti

l

vit

rect

om

y(n

=1

0

2ndash

18

0

day

saf

ter

dia

gn

osi

s)

91

1(6

mo

nth

s)

Ess

man

etal

17

9re

tro

spec

tiv

eCalbicansCtropicalis

5u

nsp

ecif

ied

un

spec

ifie

dv

itre

cto

myndash

loca

lA

MB

55

(25

ndash1

15

mo

nth

s)

Ch

rist

mas

etal

17

8p

rosp

ecti

ve

CalbicansCtropicalis

51

00

ndash2

00

3ndash

6w

eek

sv

itre

cto

my

55

(4ndash

11

mo

nth

s)

Ak

leret

al

17

7re

tro

spec

tiv

eu

nsp

ecif

ied

6to

tal

med

ian

do

se

=9

97

5m

g

med

ian

=5

2d

ays

AM

Biv

lt5

00

mg

+

vit

rect

om

y

1

56

re

lap

se

1(pound

6w

eek

s)

Lu

ttru

llet

al

17

6re

tro

spec

tiv

eCalbicans

(n=

2)

un

spec

ifie

d(n

=2

)

42

00

ndash4

00

4w

eek

s(n

=3

)v

itre

cto

my

1

44

(3ndash

25

mo

nth

sn

=3

)

del

Pal

acio

etal

17

5re

tro

spec

tiv

eCalbicans

74

00

(1d

ay)

then

20

03

wee

ks

ndash6

7(v

itre

cto

my

refu

sal

in

1p

atie

nt)

(Dagger6

mo

nth

s)

Kau

ffm

anet

al

17

4re

tro

spec

tiv

e

len

sim

pla

nts

Cparapsilosis

44

00

(20

0in

pat

ien

ts

wit

hre

nal

fail

ure

)

1y

ear

fail

ure

of

loca

lA

MB

rela

pse

ifn

ole

ns

abla

tio

n

(2y

ears

afte

rst

op

pin

g)

AM

B

amphote

rici

nB

iv

in

trav

enous

Review

401

Table

14

Rep

ort

so

fp

atie

nts

wit

hen

do

card

itis

du

eto

Candida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Val

vu

lar

inv

olv

emen

tCandida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Dose

of

fluco

naz

ole

(mg

day

)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y(f

oll

ow

-up

du

rati

on

)

Ino

ueet

al

18

2ao

rtic

val

ve

Cparapsilosis

16

00

then

40

01

8m

on

ths

surg

ery

reco

ver

y(1

8m

on

ths)

Lej

ko

-Zu

pan

cet

al

19

7m

itra

lp

rost

hes

isCparapsilosis

14

00

(14

day

s)th

en1

00

8m

on

ths

AM

B(3

9g

)A

BC

D

(15

g)

no

rep

lace

men

t

reco

ver

y(gt

3y

ears

)

Joly

etal

19

8p

acem

aker

Calbicans

14

00

(6d

ays)

then

20

07

mo

nth

ssu

rger

yre

cov

ery

(18

mo

nth

s)

Ng

uy

enet

al

19

6ao

rtic

pro

sth

esis

Calbicans

14

00

then

20

04

5y

ears

AM

B+

5F

C

12

wee

ks

no

rep

lace

men

t

reco

ver

y(5

5y

ears

)

Gil

ber

tet

al

19

5ao

rtic

pro

sth

esis

Calbicans

12

00

8m

on

ths

surg

ery

AM

B(2

g)

+

5F

C

40

day

s

reco

ver

y(9

mo

nth

s)

Wel

lset

al

19

4m

itra

lan

dtr

icu

spid

val

ves

Calbicans

12

00

ndash4

00

(14

day

s)

then

40

0th

en5

0

65

mo

nth

s

(40

0m

g)

and

10

mo

nth

s

(50

mg

)

no

rep

lace

men

tre

cov

ery

(45

yea

rs)

Zah

idet

al

19

3m

itra

lv

alv

e

(pro

bab

le)

Cparapsilosis

14

00

18

mo

nth

sA

MB

(5g

)+

5F

C

ket

oco

naz

ole

(80

0m

gd

ay

4m

on

ths)

no

rep

lace

men

t

reco

ver

y(5

yea

rs)

Can

cela

set

al

19

2m

itra

lv

alv

eCparapsilosis

12

00

4m

on

ths

surg

ery

A

MB

(2g

)re

cov

ery

(4m

on

ths)

Th

aku

ret

al

19

1ao

rtic

pro

sth

esis

Calbicans

12

00

6w

eek

sA

MB

(30

mg

day

)

6w

eeks

no

repla

cem

ent

reco

ver

y(2

6m

on

ths)

Czw

erw

iecet

al

19

0ao

rtic

pro

sth

esis

Cparapsilosis

14

00

26

mo

nth

sA

MB

(72

5m

g)

no

rep

lace

men

t

reco

ver

y(2

6m

on

ths)

Ota

kiet

al

18

9m

itra

lp

rost

hes

isCparapsilosis

1u

nsp

ecif

ied

68

day

sn

ore

pla

cem

ent

fail

ure

(dea

thd

ue

toce

reb

ral

hae

mo

rrh

age

and

fev

er)

Wal

lbri

dg

eet

al

18

8m

itra

lp

rost

hes

isCparapsilosis

12

00

-40

0gt

7w

eek

sA

MB

(30

0m

g)

no

rep

lace

men

t

reco

ver

y(6

mo

nth

s)

Ven

dit

tiet

al

18

7in

tera

tria

lse

ptu

mCalbicans

12

00

(28

day

s)th

en6

00

(11

day

s)th

en4

00

6m

on

ths

no

rep

lace

men

tre

cov

ery

(14

mo

nth

s)

Her

nan

dez

etal

18

6m

itra

lv

alv

eCalbicans

12

00

3m

on

ths

AM

Bfa

ilu

ren

o

rep

lace

men

t

imp

rov

emen

t(3

mo

nth

s)

Ro

up

ieet

al

18

5ao

rtic

val

ve

Ctropicalis

14

00

50

day

sn

ore

pla

cem

ent

reco

ver

y(1

1m

on

ths)

Mar

tin

oet

al

18

4in

tera

tria

lse

ptu

mCparapsilosis

13

mg

kg

(7d

ays)

then

6m

gk

g

gt3

mo

nth

sG

M-C

SF

(gt6

wee

ks)

no

rep

lace

men

t

reco

ver

y(5

mo

nth

s)

Isal

skaet

al

18

3m

itra

lp

rost

hes

isCparapsilosis

11

00

ndash2

00

11

mo

nth

sn

ore

pla

cem

ent

reco

ver

y(1

yea

r)

AM

B

amph

ote

rici

nB

5

FC

fl

ucy

tosi

ne

AB

CD

am

ph

ote

rici

nB

coll

oid

ald

isp

ersi

on

G

M-C

SF

g

ran

ulo

cyte

ndashm

on

ocy

teco

lon

y-s

tim

ula

tin

gfa

cto

r

Review

402

favoured by indwelling urinary catheters immunosuppressivedrugs or antibiotic prescriptions diabetes mellitus and extremeages C albicans is involved in half of the cases followed byC glabrata in 15 of the cases In 10 of cases infection involvesmore than one species208 Fluconazole achieves a 10 times higherconcentration in urine than in blood with powerful effect even onCglabrata infections Therefore it represents a first line treatment ofany Candida urinary tract infection

In a randomized placebo-controlled multicentre study amongpatients with asymptomatic candiduria Sobel et al209 found thatfluconazole (200 mgday) hastened the time to negative resultsof urine cultures However the rate of negative urine cultures2 weeks after the end of therapy was similar in the fluconazole-and placebo-treated groups showing the minimal utility of treat-ment in that setting Indeed asymptomatic candiduria should betreated only in high-risk situations namely patients with neutrope-nia infants with low birth weight patients with renal allografts andpatients who will undergo urologic manipulations (recommenda-tion of grade B-III from the IDSA) The optimal regimen in thatsetting is not known Short courses regimen are not recommendedand therapy for 1ndash2 weeks should be efficient

Ascending pyelonephritis treatment should also include ade-quate urinary drainage and removal of obstructive fungusballs210 Urinary tract devices should be optimally removed orat least replaced

Haematogenous renal involvement should be treated with high-dose parenteral fluconazole (6 mgkgday) in accordance with therecently published IDSA guidelines57

Fluconazole in childreninfants

No specific approval of fluconazole has been obtained inyoung children before the age of 6 months but a few studieshave evaluated its use in several settings

Prophylaxis of systemic candidiasis in neonates

Few studies have focused on the use of fluconazole as a prophy-lactic agent against invasive candidiasis in neonates Kaufmanet al211 demonstrated in 2001 the efficacy and safety of flucona-zole (3 mgkg every 3 days during the first 2 weeks then every2 days during the following 2 weeks and then every day until thesixth week of life) in extremely low birth weight and high-riskinfants (lt1000 g) in preventing both colonization and invasivefungal infection High risk was defined as the presence of a centralvascular catheter or endotracheal tube Indeed among the 50infants randomly assigned to fluconazole the rate of colonization(22) was significantly lower than in the 50 placebo-treated ones(60) no invasive fungal infection developed in the fluconazolegroup compared with a 20 rate of infection in the placebo groupNo adverse effect of fluconazole was documented

Kicklighter et al212 similarly observed the safety of fluconazoleat 6 mgkg (for 6 weeks) and its efficacy among neonates with lowbirth weight (lt1500 g) in the prevention of rectal colonization(however occurrence of invasive candidiasis was similar inboth groups) A Cochrane review of fluconazole prophylaxis inpreterm infants demonstrated a reduced risk of invasive infection(related risk 020) and mortality (related risk 044) in fluconazole-treated patients compared with placebo-treated patients213

Although concerns about resistance to azoles have been raised

the vast majority ofCandida spp strains have remained susceptibleto fluconazole over the past decade in this population40

Fluconazole in systemic candidiasis in childreninfants

Neonatal candidaemia Candidaemia is a major cause of sepsis inneonatal ICU representing up to 16 of all sepsis cases Therelated mortality rate is high often nearly 50214 Most casesare related to C albicans and C parapsilosis with a recent risein cases related to C tropicalis The main risk factors for invasivecandidiasis among neonates are low birth weight intravascularcatheters intratracheal intubation total parenteral nutrition andadministration of intralipid solution and recent administration ofbroad-spectrum antibiotics and corticosteroids10

Treatment with amphotericin B and 5-flucytosine has been thegold standard for years However amphotericin B has some seriousside effects which makes it mandatory to consider its use in thatsetting With good profile of tolerance good diffusion in all tissuesand body fluids and reliable oral absorption fluconazole has beenstudied as an alternative (see Table 15) In 1994 Fasano et al215

reported the compassionate use of fluconazole among 40 new-borns including 11 who presented with Candida sp meningitisThey were treated with a mean daily dosage of 5 mgkgday for amean duration of 26 days Of the 32 patients with evaluable out-come 31 experienced clearance of infection Other studies haveconfirmed these results in the recent years11216ndash220 In a multicen-tre prospective randomized study Driessen et al220 compared theefficacy and safety of either amphotericin B ndash 5-flucytosine orfluconazole (oral or intravenous dose of 10 mgkg as initialdose and then 5 mgkgday) in neonates with candidaemia Inthe fluconazole group 812 (67) survived versus 611 (55) inthe other group220 Among the four patients who died in the flu-conazole group two had treatment failure versus one in the ampho-tericin B group Cytolytic hepatitis was less frequent in thefluconazole-treated group Two isolated case reports also suggestthat the association of fluconazole and flucytosine might be syn-ergistic in the treatment of neonatal candidaemia222223

Very recently Mondal et al229 compared the efficacy and safetyof oral itraconazole versus oral fluconazole (both doses of 10 mgkgday) in newborns and paediatric patients with candidaemiaSimilar cure rate (81 and 82) mortality rate (95 and 135)and number of side effects were observed224 Fluconazole thusappears as a safe and effective systemic antifungal agent in thesetting of neonatal candidiasis

Children with systemic candidiasis Excluding the setting of neo-natal candidiasis very few studies have however focused on thepaediatric population when studying the efficiency of fluconazolefor the treatment of invasive candidiasis

In 1991 Viscoli et al reported the outcome of 24 immunocom-promised children treated with fluconazole (6 mgkgday) for 34episodes of proven invasive candidiasis A total of 3034 clinicaland microbiological cures were achieved Two patients with fun-gaemia due toC parapsilosis required an increase in dosage of up to12 mgkg Transient drug-related increases of liver transaminasesoccurred in two cases (6)225 In 1994 Fasano et al reported theoutcome of 63 children with AIDS cancer or transplantationprospectively receiving fluconazole as compassionate treatment(dose regimen ranging from 016 to 11 mgkgday mean 34 mgkgday)215 Half of them had fungaemia while the others hadrespiratory urinary tract or superficial oropharyngeal infections

Review

403

Clinical cure or improvement was achieved in 5263 (83) andpathogen eradication was achieved in 4359 (73)17 Huttovaet al218 reported in 1998 the outcome of 10 children withnosocomial fungal meningitis including 8 cases of candidal men-ingitis treated using fluconazole Five of them survived with clinicaland microbiological cure

Conclusions

Almost 15 years after its launch fluconazole remains a cornerstoneof antifungal prophylaxis and therapy of invasive candidiasis It hasan excellent pharmacokinetic and safety profile even in debilitatedpatients with good tissue penetration and a lack of major druginteractions particularly with immunosuppressive agents It can beprescribed in patients with renal failure if daily dosages are adaptedto the creatinine serum level Its spectrum of antimicrobial efficacyis reasonable and it remains active against most intrinsically sus-ceptible Candida spp encountered in systemic disease with lt5of C albicans resistant to fluconazole in that setting Although Ckrusei is intrinsically resistant to fluconazole it is rarely reported asa cause of systemic infection outside neutropenic patients Thus Cglabrata is the only species which might now limit the use offluconazole for the first line therapy of yeast fungaemia whenthe species is not identified Similarly patients who recentlyreceived fluconazole as antifungal prophylaxis should not be trea-ted with fluconazole for the curative treatment of a presumed orproven episode of systemic candidiasis The fungistatic effect offluconazole against Candida spp does not appear to influence theoutcome of candidaemic episodes at least in comparison withamphotericin B which is apparently fungicidal against Candidaspp Finally when summarizing its valuable properties the strongdemonstration of its efficacy in large randomized controlled trialsand selected clinical series its availability in various commercialpresentations and its current low cost fluconazole still remains aleading antifungal drug against susceptible Candida species

Transparency declarations

C C E H A L P R and F D have no conflicts to declareD W D In the past 5 years D W D has received grant supportfrom Astellas Merck Pfizer F2G OrthoBiotech Indevus Basileathe Fungal Research Trust the Wellcome Trust the National Insti-tute of Allergy and Infectious Diseases and the European Union Hehas been an advisorconsultant to Merck Basilea Vicuron (nowPfizer) Schering Plough Indevus F2G Nektar Daiichi SigmaTau Astellas PPL Therapeutics and Uriach He has been paid fortalks on behalf of Astellas Merck and Pfizer He holds foundershares in F2G Ltd and GBE Diagnostics Ltd and talks on behalf ofAstellas Merck and Gilead Sciences O L Speakers bureau forPfizer

References

1 Richardson K The discovery and profile of fluconazole J Chemo-

ther 1990 2 51ndash4

2 Richardson K Brammer KW Marriott MS et al Activity of

UK-49858 a bis-triazole derivative against experimental infections

with Candida albicans and Trichophyton mentagrophytes Antimicrob

Agents Chemother 1985 27 832ndash5

3 Vanrsquot Wout JW Mattie H van Furth R A prospective study of the

efficacyof fluconazole (UK-49858)againstdeep-seated fungal infections

J Antimicrob Chemother 1988 21 665ndash72Table

15

No

n-c

om

par

ativ

est

ud

ies

on

flu

con

azo

leas

cura

tiv

etr

eatm

ent

of

neo

nat

alca

nd

idae

mia

Ref

eren

ce

Nu

mb

ero

f

pat

ien

tsR

egim

enM

icro

bio

log

ical

cure

Sid

eef

fect

s

Dri

esse

net

al

22

02

1v

ery

low

bir

thw

eig

ht

5m

gk

gfo

r

1ndash

42

day

sm

ean

16

90

3

0

cyto

lyti

ch

epat

itis

Fas

anoet

al

21

54

05

mg

kg

for

2ndash

80

day

sm

ean

26

97

5

cy

toly

tic

hep

atit

is

Wai

ner

etal

21

61

91

0m

gk

go

nd

ay1

then

5m

gk

g

63

su

rviv

ing

32

fun

gal

free

dea

ths

NS

Hu

anget

al

21

71

8v

ery

low

bir

thw

eig

ht

3ndash

10

mg

kg

for

15

ndash1

73

day

sm

ean

34

6fi

rst

lin

etr

eatm

ent

83

13

afte

rA

MB

fail

ure

6

2

29

cy

toly

tic

hep

atit

is

Hu

tto

vaet

al

21

84

0v

ery

low

bir

thw

eig

ht

6m

gk

gfo

r6

ndash4

8d

ays

65

cu

rew

ith

ou

tre

lap

se5

cy

toly

tic

hep

atit

is

5

-ele

vat

edse

rum

crea

tin

ine

Gu

rpin

aret

al

21

92

42

ndash1

6m

gk

gfo

r

5ndash

72

day

sm

ean

25

96

8

an

aem

iao

rcy

toly

tic

hep

atit

is

Sch

war

zeet

al

11

53

5ndash

6m

gk

gfo

r3

wee

ks

mea

n2

17

8

4

cyto

lyti

ch

epat

itis

AM

B

amphote

rici

nB

ver

ylo

wbir

thw

eight

lt1500

g

NS

st

atis

tica

lly

not

signif

ican

t

Review

404

4 Vanrsquot Wout JW deGraeff-Meeder ER Paul LC et al Treatment of

two cases of cryptococcal meningitis with fluconazole Scand J Infect Dis

1988 20 193ndash8

5 Tucker RM Williams PL Arathoon EG et al Pharmacokinetics of

fluconazole in cerebrospinal fluid and serum in human coccidioidal

meningitis Antimicrob Agents Chemother 1988 32 369ndash73

6 ByrneWRWajszczukCPCryptococcalmeningitis in theacquired

immunodeficiency syndrome (AIDS) successful treatment with flucona-

zole after failure of amphotericin B Ann Intern Med 1988 108 384ndash5

7 HughesCE BeggsWH Action of fluconazole (UK-49858) in rela-

tion to other systemic antifungal azoles J Antimicrob Chemother 1987

19 171ndash4

8 DebruyneDClinicalpharmacokineticsof fluconazole insuperficial

and systemic mycoses Clin Pharmacokinet 1997 33 52ndash77

9 Brammer KW Coates PE Pharmacokinetics of fluconazole in

pediatric patients Eur J Clin Microbiol Infect Dis 1994 13 325ndash9

10 Schwarze R Penk A Pittrow L Administration of fluconazole in

children below 1 year of age Mycoses 1999 42 3ndash16

11 Schwarze R Penk A Pittrow L Treatment of candidal infections

with fluconazole in neonates and infants Eur J Med Res 2000 5 203ndash8

12 Thaler FBernardBTodMet al Fluconazolepenetration in cereb-

ral parenchyma in humans at steady stateAntimicrob Agents Chemother

1995 5 1154ndash6

13 Bozzette SA Gordon RL Yen A et al Biliary concentrations of

fluconazole in a patient with candidal cholecystitis case reportClin Infect

Dis 1992 4 701ndash3

14 Debruyne D Ryckelynck JP Moulin M et al Pharmacokinetics of

fluconazole in patients undergoing continuous ambulatory peritoneal dial-

ysis Clin Pharmacokinet 1990 18 491ndash8

15 Tod M Lortholary O Padoin C et al Intravenous penetration of

fluconazole during endophthalmitis Clin Microbiol Infect 1997 3 143ndash4

16 Urbak SF Degn T Fluconazole in the management of fungal ocu-

lar infections Ophthalmologica 1994 3 147ndash56

17 Fasano C OrsquoKeefe J Gibbs D Fluconazole treatment of children

with severe fungal infections not treatable with conventional agentsEur J

Clin Microbiol Infect Dis 1994 13 344ndash7

18 Aleck KA Bartley DL Multiple malformation syndrome following

fluconazole use in pregnancy report of an additional patient Am J Med

Genet 1997 72 253ndash6

19 Buijk SL Gyssens IC Mouton JW et al Pharmacokinetics of

sequential intravenous and enteral fluconazole in critically ill surgical

patients with invasive mycoses and compromised gastro-intestinal func-

tion Intensive Care Med 2001 27 115ndash21

20 El-Yazigi AEllisMErnstPet al Pharmacokinetics of oral flucona-

zole when used for prophylaxis in bone marrow transplant recipients

Antimicrob Agents Chemother 1997 41 914ndash17

21 Finch CK Green CA Self TH Fluconazole-carbamazepine inter-

action South Med J 2002 95 1099ndash100

22 Tucker RM Denning DW Hanson RH et al Interaction of azoles

with rifampin phenytoin and carbamazepine in vitro and clinical obser-

vations Clin Infect Dis 1992 14 165ndash74

23 Stockley IH Stockleyrsquos Drug Interactions A Source Book of Inter-

actions Their Mechanisms Clinical Importance and Management 6th

edn London UK Pharmaceutical Press 2002

24 von Moltke LL Greenblatt DJ Duan SX et al Inhibition of terfena-

dine metabolism in vitro by azole antifungal agents and by selective sero-

tonin reuptake inhibitor antidepressants relation to pharmacokinetic

interactions in vivo J Clin Psychopharmacol 1996 16 104ndash12

25 BrockmeyerNH Tillmann I Mertins L et al Pharmacokinetic inter-

action of fluconazole and zidovudine in HIV-positive patients Eur J Med

Res 1997 2 377ndash83

26 van Burik JA LeisenringW Myerson D et al The effect of prophy-

lactic fluconazole on the clinical spectrum of fungal diseases in bone

marrow transplant recipients with special attention to hepatic candidiasis

An autopsy study of 355 patients Medicine 1998 77 246ndash54

27 Wingard JR Antifungal chemoprophylaxis after blood andmarrow

transplantation Clin Infect Dis 2002 34 1386ndash90

28 GarbinoJLewDPRomandJAetalPreventionofsevereCandida

infections in nonneutropenic high-risk critically ill patients a randomized

double-blind placebo-controlled trial in patients treatedbyselectivediges-

tive decontamination Intensive Care Med 2002 28 1708ndash17

29 Gearhart MO Worsening of liver function with fluconazole and

review of azole antifungal hepatotoxicity Ann Pharmacother 1994 281177ndash81

30 Crerar-Gilbert A Boots R Fraenkel D et al Survival following ful-

minant hepatic failure from fluconazole induced hepatitis Anaesth Inten-

sive Care 1999 27 650ndash2

31 PappasPGKauffmanCAPerfect Jetal Alopeciaassociatedwith

fluconazole therapy Ann Intern Med 1995 123 354ndash7

32 Stevens DA Diaz M Negroni R et al Safety evaluation of chronic

fluconazole therapy Fluconazole Pan-American Study Group

Chemotherapy 1997 5 371ndash7

33 Anaissie EJ Kontoyiannis DP Huls C et al Safety plasma con-

centrations and efficacy of high-dose fluconazole in invasive mold infec-

tions J Infect Dis 1995 172 599ndash602

34 Gussenhoven MJ Haak A Peereboom-Wynia JD et al Stevens-

Johnson syndrome after fluconazole Lancet 1991 338 120

35 NovelliVHolzelHSafetyand tolerabilityof fluconazole inchildrenAntimicrob Agents Chemother 1999 43 1955ndash60

36 Koks CH Crommentuyn KM Hoetelmans RM et al Can

fluconazole concentrations in saliva be used for therapeutic drug mon-

itoring Ther Drug Monit 2001 4 449ndash53

37 Louie A Drusano GL Banerjee P et al Pharmacodynamics of

fluconazole in amurinemodel of systemic candidiasisAntimicrob Agents

Chemother 1998 42 1105ndash9

38 PittrowLPenkAPlasmaand tissueconcentrationsof fluconazole

and their correlation to breakpoints Mycoses 1997 40 25ndash32

39 Rex JH Pfaller MA Galgiani JN et al Development of interpretive

breakpoints forantifungalsusceptibility testing conceptual frameworkand

analysis of in vitro-in vivo correlation data for fluconazole itraconazole

and Candida infections Subcommittee on Antifungal Susceptibility Test-

ingof theNationalCommittee forClinical LaboratoryStandardsClin Infect

Dis 1997 24 235ndash47

40 Pfaller MA Diekema DJ Twelve years of fluconazole in clinical

practiceglobal trends inspeciesdistributionand fluconazolesusceptibility

of bloodstream isolatesofCandida International FungalSurveillancePar-

ticipant Group Clin Microbiol Infect 2004 10 Suppl 1 11ndash23

41 Tortorano AM Rigoni AL Biraghi E et al The European Confed-

eration of Medical Mycology (ECMM) survey of candidaemia in Italy anti-

fungal susceptibility patterns of 261 non-albicans Candida isolates from

blood J Antimicrob Chemother 2003 52 679ndash82

42 Pfaller MAMesser SA Boyken L et al Geographic variation in the

susceptibilities of invasive isolates of Candida glabrata to seven systemi-

cally active antifungal agents a global assessment from the ARTEMIS

Antifungal Surveillance Program conducted in 2001 and 2002 J Clin

Microbiol 2004 42 3142ndash6

43 Paya CV Fungal infections in solid-organ transplantation Clin

Infect Dis 1993 16 677ndash88

44 Singh N Wagener MM Marino IR et al Trends in invasive fungal

infections in liver transplant recipients correlation with evolution in trans-

plantation practices Transplantation 2002 73 63ndash7

45 Fung JJ Fungal infection in liver transplantation Transplant InfectDis 2002 4 18ndash23

46 Winston DJ Pakrasi A Busuttil RW Prophylactic fluconazole in

liver transplant recipientsA randomized double-blind placebo-controlled

trial Ann Intern Med 1999 131 729ndash37

47 Gladdy RA Richardson SE Davies HD et al Candida infection in

pediatric liver transplant recipients Liver Transpl Surg 1999 5 16ndash24

Review

405

48 Castaldo P Stratta RJ Wood RP et al Clinical spectrum of fungal

infections after orthotopic liver transplantation Arch Surg 1991 126149ndash56

49 Husain S Tollemar J Dominguez EA et al Changes in the spec-

trum and risk factors for invasive candidiasis in liver transplant recipients

prospective multicenter case-controlled study Transplantation 2003

75 2023ndash9

50 GeorgeMJ Snydman DRWerner BG et al The independent role

of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic

liver transplant recipients Boston Center for Liver Transplantation

CMVIG-Study Group Cytogam MedImmune Inc Gaithersburg Mary-

land Am J Med 1997 103 106ndash13

51 Dockrell DH Mendez JC Jones M et al Human herpesvirus 6

seronegativity before transplantation predicts the occurrence of fungal

infection in liver transplant recipientsTransplantation 1999 67 399ndash403

52 Tollemar J Ericzon BG Barkholt L et al Risk factors for deep

Candida infections in liver transplant recipients Transplant Proc 1990

22 1826ndash7

53 Lumbreras C Cuervas-Mons V Jara P et al Randomized trial of

fluconazole versus nystatin for the prophylaxis of Candida infection

following liver transplantation J Infect Dis 1996 174 583ndash8

54 Winston DJ Busuttil RW Randomized controlled trial of oral itra-

conazole solution versus intravenousoral fluconazole for prevention of

fungal infections in liver transplant recipients Transplantation 2002

74 688ndash95

55 Tortorano AM Viviani MA PaganoA et al Candida colonization in

orthotopic liver tranplantation fuconazole versus oral amphoericin B

J Mycol Med 1995 5 21ndash4

56 Kung N Fisher N Gunson B et al Fluconazole prophylaxis for

high-risk liver transplant recipients Lancet 1995 345 1234ndash5

57 Pappas PG Rex JH Sobel JD et al Guidelines for treatment of

candidiasis Clin Infect Dis 2004 38 161ndash89

58 PayaCV Prevention of fungal infection in transplantation TransplInfect Dis 2002 4 S46ndash51

59 LortholaryO Dupont B Antifungal prophylaxis during neutropenia

and immunodeficiency Clin Microbiol Rev 1997 10 477ndash504

60 Benedetti E Gruessner AC Troppmann C et al Intra-abdominal

fungal infections after pancreatic transplantation incidence treatment

and outcome J Am Coll Surg 1996 183 307ndash16

61 LumbrerasC Fernandez I Velosa J et al Infectious complications

following pancreatic transplantation incidence microbiological and clini-

cal characteristics and outcome Clin Infect Dis 1995 20 514ndash20

62 Patterson JE Epidemiology of fungal infections in solid organ

transplant patients Transpl Infect Dis 1999 1 229ndash36

63 Kusne S Furukawa H Abu-Elmagd K et al Infectious complica-

tions after small bowel transplantation in adults an update Transplant

Proc 1996 28 2761ndash2

64 Paterson DL Ndirangu M Kwak EJ et al Opportunistic infections

in solid-organ transplant recipients pre-treated with alumetuzumab In

Abstracts of the Forty-Fourth Interscience Conference on Antimicrobial

Agents and Chemotherapy Washington DC 2004 Abstract K-1427 p

357 American Society for Microbiology Washington DC USA

65 Kramer MR Marshall SE Starnes VA et al Infectious complica-

tions in heart-lung transplantation Analysis of 200 episodes Arch Intern

Med 1993 153 2010ndash6

66 Goodrich JMReedECMori M et al Clinical features and analysis

of risk factors for invasive candidal infection after marrow transplantation

J Infect Dis 1991 164 731ndash40

67 Dykewicz CA Centers for Disease Control and Prevention (US)

Infectious Diseases Society of America American Society of Blood and

MarrowTransplantation Summary of the guidelines for preventing oppor-

tunistic infections among hematopoietic stem cell transplant recipients

Clin Infect Dis 2001 33 139ndash44

68 Sable CA Donowitz GR Infections in bone marrow transplant

recipients Clin Infect Dis 1994 18 273ndash81

69 Goodman JLWinston DJ Greenfield RA et al A controlled trial of

fluconazole to prevent fungal infections in patients undergoing bone mar-

row transplantation N Engl J Med 1992 326 845ndash51

70 Slavin MA Osborne B Adams R et al Efficacy and safety of flu-

conazole prophylaxis for fungal infectionsaftermarrow transplantationmdasha

prospective randomized double-blind study J Infect Dis 1995 1711545ndash52

71 Marr KA Seidel K SlavinMA et al Prolonged fluconazole prophy-

laxis is associated with persistent protection against candidiasis-related

death in allogeneic marrow transplant recipients long-term follow-up of a

randomized placebo-controlled trial Blood 2000 96 2055ndash61

72 AlangadenGChandrasekar PH BaileyE et al Antifungal prophy-

laxis with low-dose fluconazole during bone marrow transplantation The

Bone Marrow Transplantation Team Bone Marrow Transplant 1994 14919ndash24

73 Wolff SN Fay J Stevens D et al Fluconazole versus low-dose

amphotericin B for the prevention of fungal infections in patients under-

going bonemarrow transplantation a study of theNorthAmericanMarrow

Transplant Group Bone Marrow Transplant 2000 25 853ndash9

74 Annaloro C Oriana A Tagliaferri E et al Efficacy of different pro-

phylactic antifungal regimens in bone marrow transplantation Haemato-

logica 1995 80 512ndash17

75 Winston DJ Maziarz RT Chandrasekar PH et al Intravenous and

oral itraconazole versus intravenous and oral fluconazole for long-term

antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant

recipients A multicenter randomized trial Ann Intern Med 2003 138705ndash13

76 MarrKACrippaF LeisenringWet al Itraconazoleversus flucona-

zole forpreventionof fungal infections inpatients receivingallogeneicstem

cell transplants Blood 2004 103 1527ndash33

77 MacMillan ML Goodman JL DeFor TE et al Fluconazole to pre-

vent yeast infections in bone marrow transplantation patients a random-

ized trial of high versus reduced dose and determination of the value of

maintenance therapy Am J Med 2002 112 369ndash79

78 Marr KA Seidel K White TC et al Candidemia in allogeneic blood

and marrow transplant recipients evolution of risk factors after the adop-

tion of prophylactic fluconazole J Infect Dis 2000 181 309ndash16

79 van Burik JA Ratanatharathorn V Stepan DE et al Micafungin

versus fluconazole for prophylaxis against invasive fungal infections dur-

ing neutropenia in patients undergoing hematopoietic stem cell trans-

plantation Clin Infect Dis 2004 39 1407ndash16

80 Prentice HG Kibbler CC Prentice AG Towards a targeted risk-

based antifungal strategy in neutropenic patients Br J Haematol 2000

110 273ndash84

81 Laverdiere M Rotstein C Bow EJ et al Impact of fluconazole

prophylaxis on fungal colonizatin and infection rates in neutropenic

patients The Canadian Fluconazole Study J Animicrob Chemother

2000 46 1001ndash8

82 Winston DJ Chandrasekar PH Lazarus HM et al Fluconazole

prophylaxis of fungal infections in patients with acute leukemia Results

of a randomized placebo-controlled double-blind multicenter trial Ann

Intern Med 1993 118 495ndash503

83 Chandrasekar PHGatnyCMEffect of fluconazole prophylaxis on

fever and use of amphotericin in neutropenic cancer patients Bone Mar-

row Transplantation Team Chemotherapy 1994 40 136ndash43

84 Rotstein C Bow EJ Laverdiere M et al Randomized placebo-

controlled trial of fluconazole prophylaxis for neutropenic cancer patients

benefit basedonpurposeand intensity of cytotoxic therapy TheCanadian

Fluconazole Prophylaxis Study Group Clin Infect Dis 1999 28 331ndash40

85 YamacK Senol E HaznedarR Prophylactic use of fluconazole in

neutropenic cancer patients Postgrad Med J 1997 71 284ndash6

86 KernW BehreG Rudolf T et al Failure of fluconazole prophylaxis

to reducemortality or the requirement of systemic amphotericin B therapy

during treatment for refractory acute myeloid leukemia results of a

Review

406

prospective randomized phase III study German AML Cooperative

Group Cancer 1998 83 291ndash301

87 SchaffnerA SchaffnerM Effect of prophylactic fluconazole on the

frequencyof fungal infectionsamphotericinBuseandhealthcarecosts in

patients undergoing intensive chemotherapy for hematologic neoplasias

J Infect Dis 1995 172 1035ndash41

88 Egger T Gratwohl A Tichelli A et al Comparison of fluconazole

with oral polyenes in the prevention of fungal infections in neutropenic

patients A prospective randomized single-center study Support Care

Cancer 1995 3 139ndash46

89 Morgenstern GR Prentice AG Prentice H et al A randomized

controlled trial of itraconazole versus fluconazole for the prevention of

fungal infections in patients with haematological malignancies UK Mul-

ticentre Antifungal Prophylaxis Study Group Br J Haematol 1999 105901ndash11

90 EllisMEClinkHErnstPetalControlledstudyof fluconazole in the

preventionof fungal infections in neutropenic patientswith haematological

malignancies and bone marrow transplant recipients Eur J Clin Microbiol

Infect Dis 1994 13 3ndash11

91 Philpott-Howard JN Wade JJ Mufti GJ et al Randomized com-

parisonoforal fluconazoleversusoralpolyenes for thepreventionof fungal

infection in patients at risk of neutropenia Multicentre Study Group

J Antimicrob Chemother 1993 31 973ndash84

92 Ninane J A multicentre study of fluconazole versus oral polyenes

in the prevention of fungal infection in children with hematological or

oncological malignancies Multicentre Study Group Eur J Clin Microbiol

Infect Dis 1994 13 330ndash7

93 Menichetti F Del Favero A Martino P et al Preventing fungal

infection in neutropenic patients with acute leukemia fluconazole com-

pared with oral amphotericin B The GIMEMA Infection Program Ann

Intern Med 1994 120 913ndash18

94 Akiyama H Mori S Tanikawa S et al Fluconazole versus oral

amphotericin B in preventing fungal infection in chemotherapy-induced

neutropenic patients with haematological malignancies Mycoses 1996

36 373ndash8

95 Meunier F AounM JanssensM et al Chemoprophylaxis of fungal

infections in granulocytopenic patients using fluconazole versus oral

amphotericin B Drug Invest 1991 3 258ndash65

96 Rozenberg-Arska M Dekker AW Branger J et al A randomized

study to compare oral fluconazole to amphotericin B in the prevention of

fungal infections inpatientswithacute leukaemiaJAntimicrobChemother

1991 27 369ndash76

97 Brammer KW Management of fungal infection in neutropenic

patients with fluconazole Haematol Blood Transfus 1990 33 546ndash50

98 Bodey GP Anaissie EJ Elting LS et al Antifungal prophylaxis

during remission induction therapy for acute leukemia fluconazole versus

intravenous amphotericin B Cancer 1994 73 2099ndash106

99 Kanda Y Yamamoto R Chizuka A et al Prophylactic action of

oral fluconazole against fungal infection in neutropenic patients A

meta-analysis of 16 randomized controlled trials Cancer 2000 891611ndash25

100 Bow EJ Laverdiere M Lussier N et al Antifungal prophylaxis for

severely neutropenic chemotherapy recipients a meta analysis of

randomized-controlled clinical trials Cancer 2002 94 3230ndash46

101 Viscoli C Paesmans M Sanz M et al Association between

antifungal prophylaxis and rate of documented bacteremia in febrile

neutropenic cancer patients Clin Infect Dis 2001 32 1532ndash7

102 HughesWT Armstrong D BodeyGP et al 2002 guidelines for the

use of antimicrobial agents in neutropenic patients with cancerClin Infect

Dis 2002 34 730ndash51

103 Cornely OA Bohme A Buchheidt D et al Prophylaxis of invasive

fungal infections in patients with hematological malignancies and solid

tumorsmdashguidelines of the Infectious Diseases Working Party (AGIHO)

of the German Society of Hematology and Oncology (DGHO) Ann

Hematol 2003 82 Suppl 2 186ndash200

104 McNeil MM Nash SL Hajjeh RA et al Trends in mortality due to

invasivemycotic diseases in theUnitedStates 1980ndash1997Clin InfectDis

2001 33 641ndash7

105 KibblerCCSeatonSBarnesRA et alManagement and outcome

of bloodstream infections due to Candida species in England and Wales

J Hosp Infect 2003 54 18ndash24

106 Marchetti O Bille J Fluckiger U et al Fungal Infection Network of

Switzerland Epidemiology of candidemia in Swiss tertiary care hospitals

secular trends 1991-2000 Clin Infect Dis 2004 38 311ndash20

107 Gudlaugsson O Gillespie S Lee K et al Attributable mortality of

nosocomial candidemia revisited Clin Infect Dis 2003 37 1172ndash7

108 Ibanez-Nolla J Nolla-Salas M Leon MA et al Early diagnosis of

candidiasis in nonneutropenic critically ill patients J Infect 2004 48181ndash92

109 BlumbergHMJarvisWRSoucieJMetalRisk factors for candidal

bloodstream infections in surgical intensive care unit patients the NEMIS

prospective multicenter study The National Epidemiology of Mycosis

Survey Clin Infect Dis 2001 33 177ndash86

110 Pittet D Monod M Suter PM et al Candida colonization and

subsequent infections in critically ill surgical patients Ann Surg 1994

220 751ndash8

111 Sendid B Poirot JL Tabouret M et al Combined detection of

mannanaemia and antimannan antibodies as a strategy for the diagnosis

of systemic infectioncausedbypathogenicCandidaspeciesJMedMicro-

biol 2002 51 433ndash42

112 Bar W Hecker H Diagnosis of systemic Candida infections in

patients of the intensive care unit Significance of serum antigens and

antibodies Mycoses 2002 45 22ndash8

113 Calandra T Marchetti O Clinical trials of antifungal prophy-

laxis among patients undergoing surgery Clin Infect Dis 2004 39S185ndash92

114 Sypula WT Kale-Pradhan PB Therapeutic dilemma of flucona-

zole prophylaxis in intensive care Ann Pharmacother 2002 36 155ndash9

115 Pelz RK Hendrix CW Swoboda SM et al Double-blind placebo-

controlled trial of fluconazole to prevent candidal infections in critically ill

surgical patients Ann Surg 2001 233 542ndash8

116 Eggimann P Francioli P Bille J et al Fluconazole prophylaxis

prevents intraabdominal candidiasis in high-risk surgical patients Crit

Care Med 1997 27 1066ndash72

117 Swoboda SM Merz WG Lipsetta PA Candidemia the impact of

antifungal prophylaxis in a surgical intensive care unitSurg Infect20034345ndash54

118 Todd JC OrsquoNeal VG Grady KP et al Reduction of secondary

mycotic infections in the trauma intensivie care unit with fluconazole

J Trauma 1991 31 1722ndash27

119 Jacobs S Price Evans DA Tariq M et al Fluconazole improves

survival in septic shock a randomized double-blind prospective studyCrit

Care Med 2003 31 1938ndash46

120 Zervos EE Fink GW Norman JG et al Fluconazole increases

bactericidal activity of neutrophils through non-cytokine-mediated path-

way J Trauma 1996 41 465ndash70

121 AblesAZBlumerNAValainisGTetal Fluconazoleprophylaxis of

severe Candida infection in trauma and postsurgical patients a prospec-

tive double-blind randomised placebo-controlled trial Infect Dis Clin

Pract 2000 9 169ndash75

122 Kam LW Lin JD Management of systemic candidal infections in

the intensive care unit Am J Health Syst Pharm 2002 59 33ndash41

123 Rocco TR Reinert SE Simms HH Effects of fluconazole admin-

istration in critically ill patients analysis of bacterial and fungal resistance

Arch Surg 2000 135 160ndash5

124 Tortorano AM Caspani L Rigoni AL et al Candidosis in the inten-

sive care unit a 20-year survey J Hosp Infect 2004 57 8ndash13

125 EggimannPGarbino J Pittet DManagement ofCandida species

infections in critically ill patients Lancet Infect Dis 2003 3 772ndash85

Review

407

126 EggimannPGarbinoJPittetDEpidemiologyofCandida species

infections incritically ill non-immunosuppressedpatientsLancet InfectDis

2003 3 685ndash702

127 Martins MD Lozano-Chiu M Rex JH Declining rates of oropha-

ryngeal candidiasis and carriage of Candida albicans associated with

trends toward reduced rates of carriage of fluconazole-resistant C albi-

cans in human immunodeficiency virus-infected patients Clin Infect Dis

1998 27 1291ndash4

128 Powderly WG Finkelstein D Feinberg J et al A randomized trial

comparing fluconazole with clotrimazole troches for the prevention of fun-

gal infections in patients with advanced human immunodeficiency virus

infection NIAID AIDS Clinical Trials Group N Engl J Med 1995 332700ndash5

129 Leen CL Dunbar EM Ellis ME et al Once-weekly fluconazole to

prevent recurrenceof oropharyngeal candidiasis inpatientswithAIDSand

AIDS-related complex a double-blind placebo-controlled study J Infect

1990 21 55ndash60

130 Stevens DA Greene SI Lang OS Thrush can be prevented in

patients with acquired immunodeficiency syndrome and the acquired

immunodeficiency syndrome-related complex Randomized double-

blind placebo-controlled study of 100-mg oral fluconazole daily Arch

Intern Med 1991 151 2458ndash64

131 Just-Nubling G Gentschew G Meissner K Fluconazole prophy-

laxis of recurrent oral candidiasis inHIV-positive patientsEur JClinMicro-

biol Infect Dis 1991 10 917ndash21

132 Marriott DJ Jones PD Hoy JF et al Fluconazole once a week as

secondary prophylaxis against oropharyngeal candidiasis in HIV-infected

patients A double-blind placebo-controlled studyMed J Aust 1993 158312ndash16

133 Schuman P Capps L Peng G et al Weekly fluconazole for the

prevention ofmucosal candidiasis inwomenwithHIV infection A random-

ized double-blind placebo-controlled trial Terry Beirn Community Pro-

grams for Clinical Research on AIDSAnn InternMed 1997 126 689ndash96

134 Havlir DV DubeMPMcCutchan JA et al Prophylaxis with weekly

versus daily fluconazole for fungal infections in patients with AIDS Clin

Infect Dis 1998 27 1369ndash75

135 Pagani JL Chave JP Casjka C et al Efficacy tolerability and

development of resistance in HIV-positive patients treated with flucona-

zole for secondary prevention of oropharyngeal candidiasis a random-

ized double-blind placebo-controlled trial JAntimicrobChemother 2002

50 231ndash40

136 Vazquez JA Peng G Sobel JD et al Evolution of antifungal sus-

ceptibility amongCandidaspecies isolates recovered fromhuman immun-

odeficiency virus-infected women receiving fluconazole prophylaxis Clin

Infect Dis 2001 33 1069ndash75

137 Delfraissy JF Prise en charge therapeutique des patients infectespas le VIH Rapport Delfraissy Paris Flammarion 2004

138 DePauwBERaemaekers JMDonnelly JPet al Anopenstudyon

the safety and efficacy of fluconazole in the treatment of disseminated

Candida infections in patients treated for hematological malignancy Ann

Hematol 1995 70 83ndash7

139 Anaissie EJ Vartivarian SE Abi-Said D et al Fluconazole versus

amphotericin B in the treatment of hematogenous candidiasis a matched

cohort study Am J Med 1996 101 170ndash6

140 Anaissie EJ Darouiche RO Abi-Said D et al Management of

invasive candidal infections results of a prospective randomized multi-

center study of fluconazole versus amphotericin B and review of the

literature Clin Infect Dis 1996 23 964ndash72

141 Myoken Y Kyo T Kohara T et al Breakthrough fungemia caused

by azole-resistant Candida albicans in neutropenic patients with acute

leukemia Clin Infect Dis 2003 36 1496ndash7

142 Anttila VJ FarkkilaM JanssonSE et al Diagnostic laparoscopy in

patientswith acute leukemiaandsuspectedhepatic candidiasisEur JClin

Microbiol Infect Dis 1997 16 637ndash43

143 Anaissie E Bodey GP Kantarjian H et al Fluconazole therapy for

chronic disseminated candidiasis in patients with leukemia and prior

amphotericin B therapy Am J Med 1991 91 142ndash50

144 KauffmanCA BradleySFRossSC et al Hepatosplenic candidia-

sis successful treatment with fluconazole Am J Med 1991 91 137ndash41

145 Kontoyiannis DP Luna MA Samuels BI et al Hepatosplenic can-

didiasis A manifestation of chronic disseminated candidiasis Infect Dis

Clin North Am 2000 14 721ndash39

146 Graninger W Presteril E Schneeweiss B et al Treatment of

Candida albicans fungaemia with fluconazole J Infect 1993 26 133ndash46

147 Phillips P Shafran S Garber G et al Multicenter randomized trial

of fluconazole versus amphotericin B for treatment of candidemia in

non-neutropenic patients Canadian Candidemia Study Group Eur J

Clin Microbiol Infect Dis 1997 16 337ndash45

148 Rex JH Bennett JE Sugar AM et alA randomized trial comparing

fluconazolewithamphotericinB for the treatmentof candidemia inpatients

without neutropenia Candidemia Study Group and the National Institute

N Engl J Med 1994 331 1325ndash30

149 Abele-Horn M Kopp A Sternberg U et al A randomized study

comparing fluconazolewith amphotericinB5-flucytosine for the treatment

of systemic Candida infections in intensive care patients Infection 1996

24 426ndash32

150 Nguyen MH Peacock JE Jr Tanner DC et al Therapeutic

approaches in patients with candidemia Evaluation in a multicenter

prospective observational study Arch Intern Med 1995 155 2429ndash35

151 Rex JH Pappas PG Karchmer AW et al A randomized and

blinded multicenter trial of high-dose fluconazole plus placebo versus flu-

conazole plus amphotericin B as therapy for candidemia and its con-

sequences in non-neutropenic subjectsClin Infect Dis 2003 36 1221ndash8

152 Mora-Duarte J Betts R Rotstein C et al Comparison of

caspofungin and amphotericin B for invasive candidiasis N Engl J Med

2002 347 2020ndash9

153 Sugar AM Saunders C Diamond RD et al Successful treatment

of Candida osteomyelitis with fluconazole A noncomparative study of

two patients Diagn Microbiol Infect Dis 1990 13 517ndash20

154 Tang C Successful treatment of Candida albicans osteomyelitis

with fluconazole J Infect 1993 26 89ndash92

155 LafontAOliveAGelmanMet alCandidaalbicansspondylodisci-

tis and vertebral osteomyelitis in patients with intravenous heroin drug

addiction Report of 3 new cases J Rheumatol 1994 21 953ndash6

156 Hennequin C Bouree P Hiesse C et al Spondylodiskitis due to

Candida albicans report of two patients who were successfully treated

with fluconazole and review of the literature Clin Infect Dis 1996 23176ndash8

157 Jonnalagadda S VeerabaguMP Rakela J et alCandida albicans

osteomyelitis in a liver transplant recipient a case report and review of the

literature Transplantation 1996 62 1182ndash4

158 Rossel P Schonheyder HC Nielsen H Fluconazole therapy

inCandidaalbicansspondylodiscitisScandJ InfectDis199830 527ndash30

159 TurnerDLJohnsonSARuleSASuccessful treatmentof candidal

osteomyelitis with fluconazole following failure with liposomal ampho-

tericin B J Infect 1999 38 51ndash3

160 El-Zaatari MM Hulten K Fares Y et al Successful treatment of

Candida albicans osteomyelitis of the spine with fluconazole and surgical

debridement case report J Chemother 2002 14 627ndash30

161 Seravalli L Van Linthoudt D Bernet C et al Candida glabrata

spinal osteomyelitis involving two contiguous lumbar vertebrae a case

report and review of the literature Diagn Microbiol Infect Dis 2003 45137ndash41

162 Garbino J Schnyder I LewDP et al An unusual cause of vertebral

osteomyelitis Candida species Scand J Infect Dis 2003 35 288ndash91

163 TunkelARThomasCYWispelweyBCandidaprostheticarthritis

report of a case treated with fluconazole and review of the literature Am J

Med 1993 94 100ndash3

Review

408

164 CushingRD FulgenziWR Synovial fluid levels of fluconazole in a

patient with Candida parapsilosis prosthetic joint infection who had an

excellent clinical response J Arthroplasty 1997 12 950

165 Fukasawa N Shirakura K Candida arthritis after total knee

arthroplastymdasha case of successful treatment without prosthesis removal

Acta Orthop Scand 1997 68 306ndash7

166 Lerch K Kalteis T Schubert T et al Prosthetic joint infections with

osteomyelitis due to Candida albicans Mycoses 2003 46 462ndash6

167 Clancy CJ Nguyen MH Morris AJ Candidal mediastinitis an

emerging clinical entity Clin Infect Dis 1997 25 608ndash13

168 PetrikkosGSkiadaA SabatakouH et al Case report Successful

treatment of two cases of post-surgical sternal osteomyelitis due to

Candida krusei and Candida albicans respectively with high doses of

triazoles (fluconazole itraconazole) Mycoses 2001 44 422ndash5

169 Weers-Pothoff GHavermans JF Kamphuis J et alCandida tropi-

calis arthritis in a patient with acutemyeloid leukemia successfully treated

with fluconazole case report and review of the literature Infection 1997

25 109ndash11

170 Laatikainen L TuominenM vonDickhoff K Treatment of endoge-

nous fungal endophthalmitis with systemic fluconazole with or without

vitrectomy Am J Ophthalmol 1992 113 205ndash7

171 Borne MJ Elliott JH OrsquoDay DM Ocular fluconazole treatment of

Candidaparapsilosisendophthalmitis after failed intravitreal amphotericin

B Arch Ophthalmol 1993 111 1326ndash7

172 Zarbin MA Becker E Witcher J et al Treatment of presumed

fungal endophthalmitis with oral fluconazole Ophthalmic Surg Lasers

1996 27 628ndash31

173 WongVK TasmanWEagleRC et al BilateralCandida parapsilo-

sis endophthalmitis Arch Ophthalmol 1997 115 670ndash2

174 Kauffman CA Bradley SF Vine AK Candida endophthalmitis

associated with intraocular lens implantation efficacy of fluconazole ther-

apy Mycoses 1993 36 13ndash17

175 del Palacio A Cuetara MS Ferro M et al Fluconazole in the man-

agement of endophthalmitis in disseminated candidosis of heroin addicts

Mycoses 1993 36 193ndash9

176 Luttrull JK Wan WL Kubak BM et al Treatment of ocular fungal

infections with oral fluconazole Am J Ophthalmol 1995 119 477ndash81

177 Akler ME Vellend H McNeely DM et al Use of fluconazole in the

treatment of candidal endophthalmitis Clin Infect Dis 1995 20 657ndash64

178 Christmas NJ Smiddy WE Vitrectomy and systemic fluconazole

for treatment of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1996 27 1012ndash18

179 EssmanTFFlynnHWSmiddyWEet al Treatment outcomes in a

10-year study of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1997 28 185ndash94

180 Martinez-Vazquez C Fernandez-Ulloa J Bordon J et al Candida

albicans endophthalmitis in brown heroin addicts response to early vit-

rectomyprecededand followedbyantifungal therapyClin InfectDis1998

27 1130ndash3

181 Aleixo MJ Caldeira L Ferreira ML Candida albicans meningitis

clinical case J Infect 2000 40 191ndash2

182 InoueY YozuR Ueda T et al A case report ofCandida parapsilo-

sis endocarditis J Heart Valve Dis 1998 7 240ndash2

183 Isalska BJ Stanbridge TN Fluconazole in the treatment of candi-

dal prosthetic valve endocarditis BMJ 1988 297 178ndash9

184 Martino P Meloni G Cassone A Candidal endocarditis and treat-

ment with fluconazole and granulocyte-macrophage colony-stimulating

factor Ann Intern Med 1990 112 966ndash7

185 Roupie E Darmon JY Brochard L et al Fluconazole therapy of

candidal native valveendocarditisEur JClinMicrobiol InfectDis199110458ndash9

186 Hernandez JA Gonzalez-Moreno M Llibre JM et al Candidal

mitral endocarditis and long-term treatment with fluconazole in a patient

with human immunodeficiency virus infection Clin Infect Dis 1992 151062ndash3

187 Venditti MDeBernardis FMicozzi A et al Fluconazole treatment

of catheter-related right-sided endocarditis caused by Candida albicans

and associated with endophthalmitis and folliculitis Clin Infect Dis 1992

14 422ndash6

188 Wallbridge DR McCartney AC Richardson MD Fluconazole in

the treatment ofCandidaprosthetic valveendocarditisMycoses199336259ndash61

189 Otaki M Kitamura N Candida prosthetic valve endocarditis An

autopsy review Int Surg 1993 78 252ndash3

190 Czwerwiec FS Bilsker MS Kamerman ML et al Long-term sur-

vival after fluconazole therapy of candidal prosthetic valve endocarditis

Am J Med 1993 94 545ndash6

191 Thakur RK Skelcy KM Kahn RN et al Successful treatment of

Candida prosthetic valve endocarditis with a combination of fluconazole

and amphotericin B Crit Care Med 1994 22 712ndash14

192 Cancelas JA Lopez JCabezudoE et al Native valve endocarditis

due toCandida parapsilosis a late complication after bonemarrow trans-

plantation-related fungemia Bone Marrow Transplant 1994 13 333ndash4

193 Zahid MA Klotz SA Hinthorn DR Medical treatment of recurrent

candidemia in a patient with probable Candida parapsilosis prosthetic

valve endocarditis Chest 1994 105 1597ndash8

194 Wells CJ Leech G Lever AM et al Treatment of native valve

Candida endocarditis with fluconazole J Infect 1995 31 233ndash5

195 Gilbert HM Peters ED Lang SJ et al Successful treatment of

fungal prosthetic valve endocarditis case report and review Clin Infect

Dis 1996 22 348ndash54

196 Nguyen MH Nguyen ML Yu VL et al Candida prosthetic valve

endocarditis prospective study of six cases and review of the literature

Clin Infect Dis 1996 22 262ndash7

197 Lejko-Zupanc T Kozelj M A case of recurrent Candida parapsilo-

sis prosthetic valve endocarditis cure bymedical treatment alone J Infect

1997 35 81ndash2

198 Joly V BelmatougN Leperre A et al Pacemaker endocarditis due

to Candida albicans case report and review Clin Infect Dis 1997 251359ndash62

199 Rex JH Walsh T Sobel JD et al Practice guidelines for the treat-

mentof candidiasis InfectiousDiseasesSocietyofAmericaClin InfectDis

2000 30 662ndash78

200 Baddour LM Long-term suppressive therapy for Candida para-

psilosis-induced prosthetic valve endocarditis Mayo Clin Proc 1995

70 773ndash5

201 Melgar GR Nasser RM Gordon SM Fungal prosthetic valve

endocarditis in 16 patients An 11-year experience in a tertiary care hos-

pital Medicine 1997 76 94ndash103

202 Dupont H Paugam-Burtz C Muller-Serieys C et al Predictive

factors of mortality due to polymicrobial peritonitis with Candida isolation

in peritoneal fluid in critically ill patients Arch Surg 2002 137 1341ndash6

203 Lee SC FungCP ChenHY et alCandida peritonitis due to peptic

ulcer perforation incidence rate risk factors prognosis and susceptibility

to fluconazole and amphotericin B Diagn Microbiol Infect Dis 2002 4423ndash7

204 Levine J Bernard DB Idelson BA et al Fungal peritonitis compli-

cating continuous ambulatory peritoneal dialysis successful treatment

with fluconazole a new orally active antifungal agent Am J Med 1989

86 825ndash7

205 Michel C Courdavault L al Khayat R et al Fungal peritonitis in

patients on peritoneal dialysis Am J Nephrol 1994 14 113ndash20

206 WangAYYuAWLi PKet al Factors predicting outcomeof fungal

peritonitis in peritoneal dialysis analysis of a 9-year experience of fungal

peritonitis in a single center Am J Kidney Dis 2000 36 1183ndash92

207 Hawkins JL Baddour LM Candida lusitaniae infections in the era

of fluconazole availability Clin Infect Dis 2003 36 14ndash18

Review

409

208 KauffmanCAVazquezJASobel JDetal Prospectivemulticenter

surveillance study of funguria in hospitalized patients The National Insti-

tute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group

Clin Infect Dis 2000 30 14ndash18

209 Sobel JD Kauffman CA McKinsey D et al Candiduria a random-

ized double-blind study of treatment with fluconazole and placebo The

National Institute of Allergy and Infectious Diseases (NIAID) Mycoses

Study Group Clin Infect Dis 2000 30 19ndash24

210 LundstromTSobel JNosocomial candiduria a reviewClin Infect

Dis 2001 32 1602ndash7

211 Kaufman D Boyle R Hazen KC et al Fluconazole prophylaxis

against fungal colonization and infection in preterm infants N Engl J

Med 2001 345 1660ndash6

212 Kicklighter SD Springer SC Cox T et al Fluconazole for the pro-

phylaxis against candidal rectal colonization in the very low birth weight

infant Pediatrics 2001 107 293ndash8

213 McGuire W Clerihew L Austin N Prophylactic intravenous anti-

fungal agents to prevent mortality and morbidity in very low birth weight

infants Cochrane Database Syst Rev 2004 CD003850

214 Agarwal JBansalSMalikGKetal Trends inneonatal septicemia

emergence of non-albicans Candida Indian Pediatr 2004 41 712ndash15

215 FasanoCOrsquoKeefe JGibbsD Fluconazole treatment of neonates

and infants with severe fungal infections not treatable with conventional

agents Eur J Clin Microbiol Infect Dis 1994 13 351ndash4

216 Wainer S Cooper PA Gouws H et al Prospective study of flu-

conazole therapy in systemicneonatal fungal infectionPediatr InfectDis J

1997 16 763ndash7

217 Huang YC Lin TY Lien RI et al Fluconazole therapy in neonatal

candidemia Am J Perinatol 2000 17 411ndash15

218 Huttova M Hartmanova I Kralinsky K et al Candida fungemia in

neonates treated with fluconazole report of forty cases including eight

with meningitis Pediatr Infect Dis J 1998 17 1012ndash15

219 Gurpinar AN Balkan E Kilic N et al Fluconazole treatment of

neonates and infants with severe fungal infections J Int Med Res 1997

25 214ndash18

220 Driessen M Ellis JB Muwazi F et al The treatment of systemic

candidiasis in neonates with oral fluconazole Ann Trop Pediatr 1997 17263ndash71

221 Driessen M Ellis JB Cooper PA et al Fluconazole vs

amphotericin B for the treatment of neonatal fungal septicemia

a prospective randomized trial Pediatr Infect Dis J 1997 151107ndash12

222 Marr B Gross S Cunningham C et al Candidal sepsis and

meningitis in a very-low-birth-weight infant successfully treated with flu-

conazole and flucytosine Clin Infect Dis 1994 19 795ndash6

223 Oleinik EM Della-Latta P Rinaldi MG et al Candida lusitaniae

osteomyelitis in a premature infant Am J Perinatol 1993 10 313ndash15

224 Mondal RK Singhi SC Chakrabarti A Randomized comparison

between fluconazole and itraconazole for the treatment of candidemia in a

pediatric intensive care unit a preliminary study Pediatr Crit Care Med

2004 5 561ndash5

225 Viscoli C Castagnola E Fioredda F et al Fluconazole in the treat-

ment of candidiasis in immunocompromised children Antimicrob Agents

Chemother 1991 35 365ndash7

226 Decruyenaere J Colardyn F Vogelaers D et al Combined use of

fluconazole and selective digestive decontamination in the prevention of

fungal infection after adult liver transplantation Transplant Proc 1995 273515ndash16

227 Koh LP Kurup A Goh YT et al Randomized trial of fluconazole

versus low-dose amphotericin B in prophylaxis against fungal infections in

patients undergoing hematopoietic stem cell transplantationAmJHema-

tol 2002 71 260ndash7

228 Gluckman E Esperou-Bourdeau H Ribaud P et al Comparaison

entre le fluconazole et le ketoconazole pour la prophylaxie des infections

fongiques chez les patients traites par greffe de moelle allogenique Cah

Oncol 1993 2 167ndash9

Review

410

response or death could be found In 1996 Anaissie et al139 com-pared the same drugs in cancer patients with candidiasis andenrolled 90 patients Doses of both fluconazole and amphotericinwere highly variable (fluconazole 200ndash600 mgday amphotericinB 03ndash12 mgkgday) The two cohorts were well matched andresponse rates at day 5 for each cohort were similar overallresponse rates were slightly better for fluconazole and therewere significantly fewer toxic effects in the fluconazole group

A more recent comparison of fluconazole versus fluconazoleplus amphotericin B in non-neutropenic subjects compared 800mgday of fluconazole versus the same dose plus 07 mgkgdayof amphotericin B in a randomized blinded multicentre trial invol-ving 219 patients151 Success rates were slightly higher and therewas a faster clearance rate of candidaemia in the combination groupcompared with fluconazole alone This suggests that the two drugsare not antagonistic and may perhaps act synergistically

Although fluconazole may be the preferred agent in non-neu-tropenic patients because of its low toxicity the recent introductionof caspofungin challenges this place particularly as it has a broaderspectrum of action A randomized study comparing caspofunginversus amphotericin B for the treatment of candidaemia in bothneutropenic and non-neutropenic patients has been completed butthere is no direct comparison with fluconazole152 Results of aprospective randomized controlled multicentre trial comparinganidulafungin a new echinocandin and fluconazole in patientswith candidaemia should be available soon

Fluconazole for the treatment of specific Candida

organ infections

All randomized studies using fluconazole to date have been under-taken in oesophageal candidiasis or candidaemia none in Candidaorgan infection although some patients with invasive candidiasishave been included in the randomized studies Therefore the datapresented here come from non-comparative open-label studies

Osteoarticular infections due to Candida sp

Very few data are available on the efficacy of fluconazole as firstline therapy in osteoarticular infections due to Candida sp Someobservations associated with spondylodiscitis have been publishedand have been summarized in Table 12153ndash162 Fluconazole (200ndash400 mgday initially gt2 months) proved to be efficacious in threecases of knee infections due to C parapsilosis163ndash165 A prostheticjoint infection and osteomyelitis of the knee due toC albicanswerecured with high doses of 800 mgday of fluconazole for 2 months incombination with repeated surgical debridement after a 10 daycourse of fluconazole 400 mgday which seemed to be ineffi-cient166 Fluconazole (400ndash800 mgday for 6 months) was alsoeffective for the treatment ofC albicans post-surgical mediastinitisin two cases167168 Fluconazole (400 mgday for 7 months) suc-cessfully treated an old patient with acute myeloid leukaemia whopresented with C tropicalis arthritis of the knee169 The latestIDSA guidelines recommend surgical debridement and initialcourse of amphotericin B for 2ndash3 weeks followed by fluconazolefor a total duration of 6ndash12 months57

Endophthalmitis due to Candida sp

A combination of partial or complete vitrectomy intraocularamphotericin B and antifungal drugs is the usual therapeuticapproach to Candida sp eye infections Several documented T

able

12

Rep

ort

so

fp

atie

nts

wit

hsp

on

dy

lod

isci

tis

du

eto

Candida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Lo

cali

zati

on

of

infe

ctio

n

Candida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Do

seo

ffl

uco

naz

ole

(mg

day

)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y

(fo

llo

w-u

pd

ura

tio

n)

Gar

bin

oet

al

16

2lu

mb

arCalbicans

14

00

3m

on

ths

(rel

apse

)

then

6m

on

ths

ndashre

cov

ery

(16

mo

nth

s)

lum

bar

Ctropicalis

18

00

foll

ow

edb

yit

raco

naz

ole

reco

ver

y(4

mo

nth

s)

Ser

aval

liet

al

16

1lu

mb

arCglabrata

18

00

3w

eek

sre

pla

ced

by

AM

B(7

0d

ays)

then

lip

idco

mp

lex

(56

day

s)

fail

ure

wit

hfl

uco

naz

ole

then

reco

ver

y(1

6m

on

ths)

El-

Zaa

tariet

al

16

0d

ors

alCalbicans

14

00

3m

on

ths

ndashre

cov

ery

(1y

ear)

Tu

rner

etal

15

9d

ors

o-l

um

bar

Calbicans

12

00

(1m

on

th)

then

10

01

2m

on

ths

afte

rfa

ilu

reo

fA

MB

li

po

som

al

AM

Ban

d5

FC

(9w

eek

s)

reco

ver

y(3

yea

rs)

Ro

ssel

etal

15

8d

ors

alCalbicans

14

00

(14

day

s)th

en2

00

7m

on

ths

afte

rfa

ilu

reo

fA

MB

(21

day

s)re

cov

ery

(1y

ear)

Jon

nal

agad

daet

al

15

7d

ors

alCalbicans

12

00

6m

on

ths

AM

B(3

g)

+5

FC

reco

ver

y(8

mo

nth

s)

Hen

neq

uin

etal

15

6lu

mb

arCalbicans

14

00

6m

on

ths

ndashre

cov

ery

(47

mo

nth

s)

lum

bar

C

alb

ican

s1

20

06

mo

nth

sndash

reco

ver

y(1

7m

on

ths)

Laf

on

tet

al

15

5lu

mb

arCalbicans

14

00

4w

eek

sndash

reco

ver

y(1

8m

on

ths)

Tan

get

al

15

4d

ors

alCalbicans

12

00

1y

ear

ndashre

cov

ery

(16

mo

nth

s)

Su

gar

etal

15

3d

ors

alan

dlu

mb

arCtropicalis

11

00

ndash1

50

1y

ear

AM

B(3

80

mg

)re

cov

ery

(26

mo

nth

s)

AM

B

amphote

rici

nB

5F

C

flucy

tosi

ne

Review

400

clinical cases reported the efficacy of fluconazole alone or incombination with other treatments in cases of endophthalmitisdue to Candida spp16170ndash173 Finally several recent series con-firmed fluconazole efficacy in cases of severe ocular infectionsdue to susceptible Candida sp in non-neutropenic patients174ndash180

Their results are summarized in Table 13 Most cases are due toC albicans and fluconazole-resistant species causing endoph-thalmitis is extremely rare On the basis of these data the IDSArecommends the use of fluconazole in this indication particularlyas follow-up therapy58

Meningitis due to Candida sp

Very few data exist on fluconazolersquos efficacy for the initial treat-ment of Candida sp meningitis in adults although this drug has avery good CSF penetration Oral fluconazole (800 mgday for3 months then 200 mgday) was successful for the treatment ofa C albicans meningitis in an HIV-infected patient with a CD4 cellcount of 35 cellsmm3 who refused intravenous therapy181

Endocarditis due to Candida sp

No series has documented the efficacy of fluconazole in endocard-itis due to Candida sp Only a few clinical cases have been pub-lished and most of these are summarized in Table 14182ndash198 Thesecases illustrate the efficacy of fluconazole (sometimes with nosurgical treatment) in endocarditis due to C albicans and alsoin endocarditis related to some non-albicans Candida spp espe-cially C parapsilosis However no study has demonstrated thesuperiority of fluconazole over amphotericin B in this indicationand there are insufficient data to recommend fluconazole as the firstline treatment for endocarditis due to Candida spp58199 Theechinocandins might have a place as primary therapy in thesecases Fluconazole (200ndash400 mgday) is often employed as partof a long-term suppressive regimen especially if valve replacementis not possible because of the high propensity for delayed relapse ofcandidal endocarditis200201

Peritonitis due to Candida sp

Peritonitis due to Candida sp may develop in patients with peri-toneal dialysis catheters or in those with surgical or traumaticinjury to the gut wall In this latter situation Candida spp areusually part of a polymicrobial infection Isolation of Candidaby direct examination of peritoneal fluid is an independent factorfor a severe outcome202 and recent small studies suggest thatprompt effective adequate and safe antifungal therapy shouldbe given in all cases of Candida sp peritonitis in order to lowerthe mortality rate and shorten the hospital stay113116 In a recentstudy of 23 cases secondary to peptic ulcer perforation the mor-tality rate in patients receiving fluconazole (200 mg intravenouslytwice daily for 2ndash4 weeks) was high (five of eight cases) probablyrelated to inadequate or too late initiation of antifungal therapy203

Some cases showing fluconazole efficacy have been reported inpatients with continuous ambulatory peritoneal dialysis eitheralone or in combination with flucytosine204ndash207 Catheter removalis crucial in these cases

Urinary infections due to Candida spp

Candida is by far the most frequent agent of urinary fungal infec-tions The line between colonization and real infection is generallyblurred Candiduria usually present as nosocomial infections T

able

13

Rep

ort

so

fp

atie

nts

wit

hen

do

ph

thal

mit

isd

ue

toCandida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Met

ho

do

log

y

of

stu

dy

Candida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Do

seo

f

flu

con

azo

le(m

gd

ay)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y

(fo

llo

w-u

pd

ura

tio

n)

Mar

tin

ez-V

azq

uez

etal

18

0p

rosp

ecti

ve

Calbicans

11

40

02

ndash8

wee

ks

AM

Biv

(n=

9)

or

no

trea

tmen

t(n

=1

)u

nti

l

vit

rect

om

y(n

=1

0

2ndash

18

0

day

saf

ter

dia

gn

osi

s)

91

1(6

mo

nth

s)

Ess

man

etal

17

9re

tro

spec

tiv

eCalbicansCtropicalis

5u

nsp

ecif

ied

un

spec

ifie

dv

itre

cto

myndash

loca

lA

MB

55

(25

ndash1

15

mo

nth

s)

Ch

rist

mas

etal

17

8p

rosp

ecti

ve

CalbicansCtropicalis

51

00

ndash2

00

3ndash

6w

eek

sv

itre

cto

my

55

(4ndash

11

mo

nth

s)

Ak

leret

al

17

7re

tro

spec

tiv

eu

nsp

ecif

ied

6to

tal

med

ian

do

se

=9

97

5m

g

med

ian

=5

2d

ays

AM

Biv

lt5

00

mg

+

vit

rect

om

y

1

56

re

lap

se

1(pound

6w

eek

s)

Lu

ttru

llet

al

17

6re

tro

spec

tiv

eCalbicans

(n=

2)

un

spec

ifie

d(n

=2

)

42

00

ndash4

00

4w

eek

s(n

=3

)v

itre

cto

my

1

44

(3ndash

25

mo

nth

sn

=3

)

del

Pal

acio

etal

17

5re

tro

spec

tiv

eCalbicans

74

00

(1d

ay)

then

20

03

wee

ks

ndash6

7(v

itre

cto

my

refu

sal

in

1p

atie

nt)

(Dagger6

mo

nth

s)

Kau

ffm

anet

al

17

4re

tro

spec

tiv

e

len

sim

pla

nts

Cparapsilosis

44

00

(20

0in

pat

ien

ts

wit

hre

nal

fail

ure

)

1y

ear

fail

ure

of

loca

lA

MB

rela

pse

ifn

ole

ns

abla

tio

n

(2y

ears

afte

rst

op

pin

g)

AM

B

amphote

rici

nB

iv

in

trav

enous

Review

401

Table

14

Rep

ort

so

fp

atie

nts

wit

hen

do

card

itis

du

eto

Candida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Val

vu

lar

inv

olv

emen

tCandida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Dose

of

fluco

naz

ole

(mg

day

)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y(f

oll

ow

-up

du

rati

on

)

Ino

ueet

al

18

2ao

rtic

val

ve

Cparapsilosis

16

00

then

40

01

8m

on

ths

surg

ery

reco

ver

y(1

8m

on

ths)

Lej

ko

-Zu

pan

cet

al

19

7m

itra

lp

rost

hes

isCparapsilosis

14

00

(14

day

s)th

en1

00

8m

on

ths

AM

B(3

9g

)A

BC

D

(15

g)

no

rep

lace

men

t

reco

ver

y(gt

3y

ears

)

Joly

etal

19

8p

acem

aker

Calbicans

14

00

(6d

ays)

then

20

07

mo

nth

ssu

rger

yre

cov

ery

(18

mo

nth

s)

Ng

uy

enet

al

19

6ao

rtic

pro

sth

esis

Calbicans

14

00

then

20

04

5y

ears

AM

B+

5F

C

12

wee

ks

no

rep

lace

men

t

reco

ver

y(5

5y

ears

)

Gil

ber

tet

al

19

5ao

rtic

pro

sth

esis

Calbicans

12

00

8m

on

ths

surg

ery

AM

B(2

g)

+

5F

C

40

day

s

reco

ver

y(9

mo

nth

s)

Wel

lset

al

19

4m

itra

lan

dtr

icu

spid

val

ves

Calbicans

12

00

ndash4

00

(14

day

s)

then

40

0th

en5

0

65

mo

nth

s

(40

0m

g)

and

10

mo

nth

s

(50

mg

)

no

rep

lace

men

tre

cov

ery

(45

yea

rs)

Zah

idet

al

19

3m

itra

lv

alv

e

(pro

bab

le)

Cparapsilosis

14

00

18

mo

nth

sA

MB

(5g

)+

5F

C

ket

oco

naz

ole

(80

0m

gd

ay

4m

on

ths)

no

rep

lace

men

t

reco

ver

y(5

yea

rs)

Can

cela

set

al

19

2m

itra

lv

alv

eCparapsilosis

12

00

4m

on

ths

surg

ery

A

MB

(2g

)re

cov

ery

(4m

on

ths)

Th

aku

ret

al

19

1ao

rtic

pro

sth

esis

Calbicans

12

00

6w

eek

sA

MB

(30

mg

day

)

6w

eeks

no

repla

cem

ent

reco

ver

y(2

6m

on

ths)

Czw

erw

iecet

al

19

0ao

rtic

pro

sth

esis

Cparapsilosis

14

00

26

mo

nth

sA

MB

(72

5m

g)

no

rep

lace

men

t

reco

ver

y(2

6m

on

ths)

Ota

kiet

al

18

9m

itra

lp

rost

hes

isCparapsilosis

1u

nsp

ecif

ied

68

day

sn

ore

pla

cem

ent

fail

ure

(dea

thd

ue

toce

reb

ral

hae

mo

rrh

age

and

fev

er)

Wal

lbri

dg

eet

al

18

8m

itra

lp

rost

hes

isCparapsilosis

12

00

-40

0gt

7w

eek

sA

MB

(30

0m

g)

no

rep

lace

men

t

reco

ver

y(6

mo

nth

s)

Ven

dit

tiet

al

18

7in

tera

tria

lse

ptu

mCalbicans

12

00

(28

day

s)th

en6

00

(11

day

s)th

en4

00

6m

on

ths

no

rep

lace

men

tre

cov

ery

(14

mo

nth

s)

Her

nan

dez

etal

18

6m

itra

lv

alv

eCalbicans

12

00

3m

on

ths

AM

Bfa

ilu

ren

o

rep

lace

men

t

imp

rov

emen

t(3

mo

nth

s)

Ro

up

ieet

al

18

5ao

rtic

val

ve

Ctropicalis

14

00

50

day

sn

ore

pla

cem

ent

reco

ver

y(1

1m

on

ths)

Mar

tin

oet

al

18

4in

tera

tria

lse

ptu

mCparapsilosis

13

mg

kg

(7d

ays)

then

6m

gk

g

gt3

mo

nth

sG

M-C

SF

(gt6

wee

ks)

no

rep

lace

men

t

reco

ver

y(5

mo

nth

s)

Isal

skaet

al

18

3m

itra

lp

rost

hes

isCparapsilosis

11

00

ndash2

00

11

mo

nth

sn

ore

pla

cem

ent

reco

ver

y(1

yea

r)

AM

B

amph

ote

rici

nB

5

FC

fl

ucy

tosi

ne

AB

CD

am

ph

ote

rici

nB

coll

oid

ald

isp

ersi

on

G

M-C

SF

g

ran

ulo

cyte

ndashm

on

ocy

teco

lon

y-s

tim

ula

tin

gfa

cto

r

Review

402

favoured by indwelling urinary catheters immunosuppressivedrugs or antibiotic prescriptions diabetes mellitus and extremeages C albicans is involved in half of the cases followed byC glabrata in 15 of the cases In 10 of cases infection involvesmore than one species208 Fluconazole achieves a 10 times higherconcentration in urine than in blood with powerful effect even onCglabrata infections Therefore it represents a first line treatment ofany Candida urinary tract infection

In a randomized placebo-controlled multicentre study amongpatients with asymptomatic candiduria Sobel et al209 found thatfluconazole (200 mgday) hastened the time to negative resultsof urine cultures However the rate of negative urine cultures2 weeks after the end of therapy was similar in the fluconazole-and placebo-treated groups showing the minimal utility of treat-ment in that setting Indeed asymptomatic candiduria should betreated only in high-risk situations namely patients with neutrope-nia infants with low birth weight patients with renal allografts andpatients who will undergo urologic manipulations (recommenda-tion of grade B-III from the IDSA) The optimal regimen in thatsetting is not known Short courses regimen are not recommendedand therapy for 1ndash2 weeks should be efficient

Ascending pyelonephritis treatment should also include ade-quate urinary drainage and removal of obstructive fungusballs210 Urinary tract devices should be optimally removed orat least replaced

Haematogenous renal involvement should be treated with high-dose parenteral fluconazole (6 mgkgday) in accordance with therecently published IDSA guidelines57

Fluconazole in childreninfants

No specific approval of fluconazole has been obtained inyoung children before the age of 6 months but a few studieshave evaluated its use in several settings

Prophylaxis of systemic candidiasis in neonates

Few studies have focused on the use of fluconazole as a prophy-lactic agent against invasive candidiasis in neonates Kaufmanet al211 demonstrated in 2001 the efficacy and safety of flucona-zole (3 mgkg every 3 days during the first 2 weeks then every2 days during the following 2 weeks and then every day until thesixth week of life) in extremely low birth weight and high-riskinfants (lt1000 g) in preventing both colonization and invasivefungal infection High risk was defined as the presence of a centralvascular catheter or endotracheal tube Indeed among the 50infants randomly assigned to fluconazole the rate of colonization(22) was significantly lower than in the 50 placebo-treated ones(60) no invasive fungal infection developed in the fluconazolegroup compared with a 20 rate of infection in the placebo groupNo adverse effect of fluconazole was documented

Kicklighter et al212 similarly observed the safety of fluconazoleat 6 mgkg (for 6 weeks) and its efficacy among neonates with lowbirth weight (lt1500 g) in the prevention of rectal colonization(however occurrence of invasive candidiasis was similar inboth groups) A Cochrane review of fluconazole prophylaxis inpreterm infants demonstrated a reduced risk of invasive infection(related risk 020) and mortality (related risk 044) in fluconazole-treated patients compared with placebo-treated patients213

Although concerns about resistance to azoles have been raised

the vast majority ofCandida spp strains have remained susceptibleto fluconazole over the past decade in this population40

Fluconazole in systemic candidiasis in childreninfants

Neonatal candidaemia Candidaemia is a major cause of sepsis inneonatal ICU representing up to 16 of all sepsis cases Therelated mortality rate is high often nearly 50214 Most casesare related to C albicans and C parapsilosis with a recent risein cases related to C tropicalis The main risk factors for invasivecandidiasis among neonates are low birth weight intravascularcatheters intratracheal intubation total parenteral nutrition andadministration of intralipid solution and recent administration ofbroad-spectrum antibiotics and corticosteroids10

Treatment with amphotericin B and 5-flucytosine has been thegold standard for years However amphotericin B has some seriousside effects which makes it mandatory to consider its use in thatsetting With good profile of tolerance good diffusion in all tissuesand body fluids and reliable oral absorption fluconazole has beenstudied as an alternative (see Table 15) In 1994 Fasano et al215

reported the compassionate use of fluconazole among 40 new-borns including 11 who presented with Candida sp meningitisThey were treated with a mean daily dosage of 5 mgkgday for amean duration of 26 days Of the 32 patients with evaluable out-come 31 experienced clearance of infection Other studies haveconfirmed these results in the recent years11216ndash220 In a multicen-tre prospective randomized study Driessen et al220 compared theefficacy and safety of either amphotericin B ndash 5-flucytosine orfluconazole (oral or intravenous dose of 10 mgkg as initialdose and then 5 mgkgday) in neonates with candidaemia Inthe fluconazole group 812 (67) survived versus 611 (55) inthe other group220 Among the four patients who died in the flu-conazole group two had treatment failure versus one in the ampho-tericin B group Cytolytic hepatitis was less frequent in thefluconazole-treated group Two isolated case reports also suggestthat the association of fluconazole and flucytosine might be syn-ergistic in the treatment of neonatal candidaemia222223

Very recently Mondal et al229 compared the efficacy and safetyof oral itraconazole versus oral fluconazole (both doses of 10 mgkgday) in newborns and paediatric patients with candidaemiaSimilar cure rate (81 and 82) mortality rate (95 and 135)and number of side effects were observed224 Fluconazole thusappears as a safe and effective systemic antifungal agent in thesetting of neonatal candidiasis

Children with systemic candidiasis Excluding the setting of neo-natal candidiasis very few studies have however focused on thepaediatric population when studying the efficiency of fluconazolefor the treatment of invasive candidiasis

In 1991 Viscoli et al reported the outcome of 24 immunocom-promised children treated with fluconazole (6 mgkgday) for 34episodes of proven invasive candidiasis A total of 3034 clinicaland microbiological cures were achieved Two patients with fun-gaemia due toC parapsilosis required an increase in dosage of up to12 mgkg Transient drug-related increases of liver transaminasesoccurred in two cases (6)225 In 1994 Fasano et al reported theoutcome of 63 children with AIDS cancer or transplantationprospectively receiving fluconazole as compassionate treatment(dose regimen ranging from 016 to 11 mgkgday mean 34 mgkgday)215 Half of them had fungaemia while the others hadrespiratory urinary tract or superficial oropharyngeal infections

Review

403

Clinical cure or improvement was achieved in 5263 (83) andpathogen eradication was achieved in 4359 (73)17 Huttovaet al218 reported in 1998 the outcome of 10 children withnosocomial fungal meningitis including 8 cases of candidal men-ingitis treated using fluconazole Five of them survived with clinicaland microbiological cure

Conclusions

Almost 15 years after its launch fluconazole remains a cornerstoneof antifungal prophylaxis and therapy of invasive candidiasis It hasan excellent pharmacokinetic and safety profile even in debilitatedpatients with good tissue penetration and a lack of major druginteractions particularly with immunosuppressive agents It can beprescribed in patients with renal failure if daily dosages are adaptedto the creatinine serum level Its spectrum of antimicrobial efficacyis reasonable and it remains active against most intrinsically sus-ceptible Candida spp encountered in systemic disease with lt5of C albicans resistant to fluconazole in that setting Although Ckrusei is intrinsically resistant to fluconazole it is rarely reported asa cause of systemic infection outside neutropenic patients Thus Cglabrata is the only species which might now limit the use offluconazole for the first line therapy of yeast fungaemia whenthe species is not identified Similarly patients who recentlyreceived fluconazole as antifungal prophylaxis should not be trea-ted with fluconazole for the curative treatment of a presumed orproven episode of systemic candidiasis The fungistatic effect offluconazole against Candida spp does not appear to influence theoutcome of candidaemic episodes at least in comparison withamphotericin B which is apparently fungicidal against Candidaspp Finally when summarizing its valuable properties the strongdemonstration of its efficacy in large randomized controlled trialsand selected clinical series its availability in various commercialpresentations and its current low cost fluconazole still remains aleading antifungal drug against susceptible Candida species

Transparency declarations

C C E H A L P R and F D have no conflicts to declareD W D In the past 5 years D W D has received grant supportfrom Astellas Merck Pfizer F2G OrthoBiotech Indevus Basileathe Fungal Research Trust the Wellcome Trust the National Insti-tute of Allergy and Infectious Diseases and the European Union Hehas been an advisorconsultant to Merck Basilea Vicuron (nowPfizer) Schering Plough Indevus F2G Nektar Daiichi SigmaTau Astellas PPL Therapeutics and Uriach He has been paid fortalks on behalf of Astellas Merck and Pfizer He holds foundershares in F2G Ltd and GBE Diagnostics Ltd and talks on behalf ofAstellas Merck and Gilead Sciences O L Speakers bureau forPfizer

References

1 Richardson K The discovery and profile of fluconazole J Chemo-

ther 1990 2 51ndash4

2 Richardson K Brammer KW Marriott MS et al Activity of

UK-49858 a bis-triazole derivative against experimental infections

with Candida albicans and Trichophyton mentagrophytes Antimicrob

Agents Chemother 1985 27 832ndash5

3 Vanrsquot Wout JW Mattie H van Furth R A prospective study of the

efficacyof fluconazole (UK-49858)againstdeep-seated fungal infections

J Antimicrob Chemother 1988 21 665ndash72Table

15

No

n-c

om

par

ativ

est

ud

ies

on

flu

con

azo

leas

cura

tiv

etr

eatm

ent

of

neo

nat

alca

nd

idae

mia

Ref

eren

ce

Nu

mb

ero

f

pat

ien

tsR

egim

enM

icro

bio

log

ical

cure

Sid

eef

fect

s

Dri

esse

net

al

22

02

1v

ery

low

bir

thw

eig

ht

5m

gk

gfo

r

1ndash

42

day

sm

ean

16

90

3

0

cyto

lyti

ch

epat

itis

Fas

anoet

al

21

54

05

mg

kg

for

2ndash

80

day

sm

ean

26

97

5

cy

toly

tic

hep

atit

is

Wai

ner

etal

21

61

91

0m

gk

go

nd

ay1

then

5m

gk

g

63

su

rviv

ing

32

fun

gal

free

dea

ths

NS

Hu

anget

al

21

71

8v

ery

low

bir

thw

eig

ht

3ndash

10

mg

kg

for

15

ndash1

73

day

sm

ean

34

6fi

rst

lin

etr

eatm

ent

83

13

afte

rA

MB

fail

ure

6

2

29

cy

toly

tic

hep

atit

is

Hu

tto

vaet

al

21

84

0v

ery

low

bir

thw

eig

ht

6m

gk

gfo

r6

ndash4

8d

ays

65

cu

rew

ith

ou

tre

lap

se5

cy

toly

tic

hep

atit

is

5

-ele

vat

edse

rum

crea

tin

ine

Gu

rpin

aret

al

21

92

42

ndash1

6m

gk

gfo

r

5ndash

72

day

sm

ean

25

96

8

an

aem

iao

rcy

toly

tic

hep

atit

is

Sch

war

zeet

al

11

53

5ndash

6m

gk

gfo

r3

wee

ks

mea

n2

17

8

4

cyto

lyti

ch

epat

itis

AM

B

amphote

rici

nB

ver

ylo

wbir

thw

eight

lt1500

g

NS

st

atis

tica

lly

not

signif

ican

t

Review

404

4 Vanrsquot Wout JW deGraeff-Meeder ER Paul LC et al Treatment of

two cases of cryptococcal meningitis with fluconazole Scand J Infect Dis

1988 20 193ndash8

5 Tucker RM Williams PL Arathoon EG et al Pharmacokinetics of

fluconazole in cerebrospinal fluid and serum in human coccidioidal

meningitis Antimicrob Agents Chemother 1988 32 369ndash73

6 ByrneWRWajszczukCPCryptococcalmeningitis in theacquired

immunodeficiency syndrome (AIDS) successful treatment with flucona-

zole after failure of amphotericin B Ann Intern Med 1988 108 384ndash5

7 HughesCE BeggsWH Action of fluconazole (UK-49858) in rela-

tion to other systemic antifungal azoles J Antimicrob Chemother 1987

19 171ndash4

8 DebruyneDClinicalpharmacokineticsof fluconazole insuperficial

and systemic mycoses Clin Pharmacokinet 1997 33 52ndash77

9 Brammer KW Coates PE Pharmacokinetics of fluconazole in

pediatric patients Eur J Clin Microbiol Infect Dis 1994 13 325ndash9

10 Schwarze R Penk A Pittrow L Administration of fluconazole in

children below 1 year of age Mycoses 1999 42 3ndash16

11 Schwarze R Penk A Pittrow L Treatment of candidal infections

with fluconazole in neonates and infants Eur J Med Res 2000 5 203ndash8

12 Thaler FBernardBTodMet al Fluconazolepenetration in cereb-

ral parenchyma in humans at steady stateAntimicrob Agents Chemother

1995 5 1154ndash6

13 Bozzette SA Gordon RL Yen A et al Biliary concentrations of

fluconazole in a patient with candidal cholecystitis case reportClin Infect

Dis 1992 4 701ndash3

14 Debruyne D Ryckelynck JP Moulin M et al Pharmacokinetics of

fluconazole in patients undergoing continuous ambulatory peritoneal dial-

ysis Clin Pharmacokinet 1990 18 491ndash8

15 Tod M Lortholary O Padoin C et al Intravenous penetration of

fluconazole during endophthalmitis Clin Microbiol Infect 1997 3 143ndash4

16 Urbak SF Degn T Fluconazole in the management of fungal ocu-

lar infections Ophthalmologica 1994 3 147ndash56

17 Fasano C OrsquoKeefe J Gibbs D Fluconazole treatment of children

with severe fungal infections not treatable with conventional agentsEur J

Clin Microbiol Infect Dis 1994 13 344ndash7

18 Aleck KA Bartley DL Multiple malformation syndrome following

fluconazole use in pregnancy report of an additional patient Am J Med

Genet 1997 72 253ndash6

19 Buijk SL Gyssens IC Mouton JW et al Pharmacokinetics of

sequential intravenous and enteral fluconazole in critically ill surgical

patients with invasive mycoses and compromised gastro-intestinal func-

tion Intensive Care Med 2001 27 115ndash21

20 El-Yazigi AEllisMErnstPet al Pharmacokinetics of oral flucona-

zole when used for prophylaxis in bone marrow transplant recipients

Antimicrob Agents Chemother 1997 41 914ndash17

21 Finch CK Green CA Self TH Fluconazole-carbamazepine inter-

action South Med J 2002 95 1099ndash100

22 Tucker RM Denning DW Hanson RH et al Interaction of azoles

with rifampin phenytoin and carbamazepine in vitro and clinical obser-

vations Clin Infect Dis 1992 14 165ndash74

23 Stockley IH Stockleyrsquos Drug Interactions A Source Book of Inter-

actions Their Mechanisms Clinical Importance and Management 6th

edn London UK Pharmaceutical Press 2002

24 von Moltke LL Greenblatt DJ Duan SX et al Inhibition of terfena-

dine metabolism in vitro by azole antifungal agents and by selective sero-

tonin reuptake inhibitor antidepressants relation to pharmacokinetic

interactions in vivo J Clin Psychopharmacol 1996 16 104ndash12

25 BrockmeyerNH Tillmann I Mertins L et al Pharmacokinetic inter-

action of fluconazole and zidovudine in HIV-positive patients Eur J Med

Res 1997 2 377ndash83

26 van Burik JA LeisenringW Myerson D et al The effect of prophy-

lactic fluconazole on the clinical spectrum of fungal diseases in bone

marrow transplant recipients with special attention to hepatic candidiasis

An autopsy study of 355 patients Medicine 1998 77 246ndash54

27 Wingard JR Antifungal chemoprophylaxis after blood andmarrow

transplantation Clin Infect Dis 2002 34 1386ndash90

28 GarbinoJLewDPRomandJAetalPreventionofsevereCandida

infections in nonneutropenic high-risk critically ill patients a randomized

double-blind placebo-controlled trial in patients treatedbyselectivediges-

tive decontamination Intensive Care Med 2002 28 1708ndash17

29 Gearhart MO Worsening of liver function with fluconazole and

review of azole antifungal hepatotoxicity Ann Pharmacother 1994 281177ndash81

30 Crerar-Gilbert A Boots R Fraenkel D et al Survival following ful-

minant hepatic failure from fluconazole induced hepatitis Anaesth Inten-

sive Care 1999 27 650ndash2

31 PappasPGKauffmanCAPerfect Jetal Alopeciaassociatedwith

fluconazole therapy Ann Intern Med 1995 123 354ndash7

32 Stevens DA Diaz M Negroni R et al Safety evaluation of chronic

fluconazole therapy Fluconazole Pan-American Study Group

Chemotherapy 1997 5 371ndash7

33 Anaissie EJ Kontoyiannis DP Huls C et al Safety plasma con-

centrations and efficacy of high-dose fluconazole in invasive mold infec-

tions J Infect Dis 1995 172 599ndash602

34 Gussenhoven MJ Haak A Peereboom-Wynia JD et al Stevens-

Johnson syndrome after fluconazole Lancet 1991 338 120

35 NovelliVHolzelHSafetyand tolerabilityof fluconazole inchildrenAntimicrob Agents Chemother 1999 43 1955ndash60

36 Koks CH Crommentuyn KM Hoetelmans RM et al Can

fluconazole concentrations in saliva be used for therapeutic drug mon-

itoring Ther Drug Monit 2001 4 449ndash53

37 Louie A Drusano GL Banerjee P et al Pharmacodynamics of

fluconazole in amurinemodel of systemic candidiasisAntimicrob Agents

Chemother 1998 42 1105ndash9

38 PittrowLPenkAPlasmaand tissueconcentrationsof fluconazole

and their correlation to breakpoints Mycoses 1997 40 25ndash32

39 Rex JH Pfaller MA Galgiani JN et al Development of interpretive

breakpoints forantifungalsusceptibility testing conceptual frameworkand

analysis of in vitro-in vivo correlation data for fluconazole itraconazole

and Candida infections Subcommittee on Antifungal Susceptibility Test-

ingof theNationalCommittee forClinical LaboratoryStandardsClin Infect

Dis 1997 24 235ndash47

40 Pfaller MA Diekema DJ Twelve years of fluconazole in clinical

practiceglobal trends inspeciesdistributionand fluconazolesusceptibility

of bloodstream isolatesofCandida International FungalSurveillancePar-

ticipant Group Clin Microbiol Infect 2004 10 Suppl 1 11ndash23

41 Tortorano AM Rigoni AL Biraghi E et al The European Confed-

eration of Medical Mycology (ECMM) survey of candidaemia in Italy anti-

fungal susceptibility patterns of 261 non-albicans Candida isolates from

blood J Antimicrob Chemother 2003 52 679ndash82

42 Pfaller MAMesser SA Boyken L et al Geographic variation in the

susceptibilities of invasive isolates of Candida glabrata to seven systemi-

cally active antifungal agents a global assessment from the ARTEMIS

Antifungal Surveillance Program conducted in 2001 and 2002 J Clin

Microbiol 2004 42 3142ndash6

43 Paya CV Fungal infections in solid-organ transplantation Clin

Infect Dis 1993 16 677ndash88

44 Singh N Wagener MM Marino IR et al Trends in invasive fungal

infections in liver transplant recipients correlation with evolution in trans-

plantation practices Transplantation 2002 73 63ndash7

45 Fung JJ Fungal infection in liver transplantation Transplant InfectDis 2002 4 18ndash23

46 Winston DJ Pakrasi A Busuttil RW Prophylactic fluconazole in

liver transplant recipientsA randomized double-blind placebo-controlled

trial Ann Intern Med 1999 131 729ndash37

47 Gladdy RA Richardson SE Davies HD et al Candida infection in

pediatric liver transplant recipients Liver Transpl Surg 1999 5 16ndash24

Review

405

48 Castaldo P Stratta RJ Wood RP et al Clinical spectrum of fungal

infections after orthotopic liver transplantation Arch Surg 1991 126149ndash56

49 Husain S Tollemar J Dominguez EA et al Changes in the spec-

trum and risk factors for invasive candidiasis in liver transplant recipients

prospective multicenter case-controlled study Transplantation 2003

75 2023ndash9

50 GeorgeMJ Snydman DRWerner BG et al The independent role

of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic

liver transplant recipients Boston Center for Liver Transplantation

CMVIG-Study Group Cytogam MedImmune Inc Gaithersburg Mary-

land Am J Med 1997 103 106ndash13

51 Dockrell DH Mendez JC Jones M et al Human herpesvirus 6

seronegativity before transplantation predicts the occurrence of fungal

infection in liver transplant recipientsTransplantation 1999 67 399ndash403

52 Tollemar J Ericzon BG Barkholt L et al Risk factors for deep

Candida infections in liver transplant recipients Transplant Proc 1990

22 1826ndash7

53 Lumbreras C Cuervas-Mons V Jara P et al Randomized trial of

fluconazole versus nystatin for the prophylaxis of Candida infection

following liver transplantation J Infect Dis 1996 174 583ndash8

54 Winston DJ Busuttil RW Randomized controlled trial of oral itra-

conazole solution versus intravenousoral fluconazole for prevention of

fungal infections in liver transplant recipients Transplantation 2002

74 688ndash95

55 Tortorano AM Viviani MA PaganoA et al Candida colonization in

orthotopic liver tranplantation fuconazole versus oral amphoericin B

J Mycol Med 1995 5 21ndash4

56 Kung N Fisher N Gunson B et al Fluconazole prophylaxis for

high-risk liver transplant recipients Lancet 1995 345 1234ndash5

57 Pappas PG Rex JH Sobel JD et al Guidelines for treatment of

candidiasis Clin Infect Dis 2004 38 161ndash89

58 PayaCV Prevention of fungal infection in transplantation TransplInfect Dis 2002 4 S46ndash51

59 LortholaryO Dupont B Antifungal prophylaxis during neutropenia

and immunodeficiency Clin Microbiol Rev 1997 10 477ndash504

60 Benedetti E Gruessner AC Troppmann C et al Intra-abdominal

fungal infections after pancreatic transplantation incidence treatment

and outcome J Am Coll Surg 1996 183 307ndash16

61 LumbrerasC Fernandez I Velosa J et al Infectious complications

following pancreatic transplantation incidence microbiological and clini-

cal characteristics and outcome Clin Infect Dis 1995 20 514ndash20

62 Patterson JE Epidemiology of fungal infections in solid organ

transplant patients Transpl Infect Dis 1999 1 229ndash36

63 Kusne S Furukawa H Abu-Elmagd K et al Infectious complica-

tions after small bowel transplantation in adults an update Transplant

Proc 1996 28 2761ndash2

64 Paterson DL Ndirangu M Kwak EJ et al Opportunistic infections

in solid-organ transplant recipients pre-treated with alumetuzumab In

Abstracts of the Forty-Fourth Interscience Conference on Antimicrobial

Agents and Chemotherapy Washington DC 2004 Abstract K-1427 p

357 American Society for Microbiology Washington DC USA

65 Kramer MR Marshall SE Starnes VA et al Infectious complica-

tions in heart-lung transplantation Analysis of 200 episodes Arch Intern

Med 1993 153 2010ndash6

66 Goodrich JMReedECMori M et al Clinical features and analysis

of risk factors for invasive candidal infection after marrow transplantation

J Infect Dis 1991 164 731ndash40

67 Dykewicz CA Centers for Disease Control and Prevention (US)

Infectious Diseases Society of America American Society of Blood and

MarrowTransplantation Summary of the guidelines for preventing oppor-

tunistic infections among hematopoietic stem cell transplant recipients

Clin Infect Dis 2001 33 139ndash44

68 Sable CA Donowitz GR Infections in bone marrow transplant

recipients Clin Infect Dis 1994 18 273ndash81

69 Goodman JLWinston DJ Greenfield RA et al A controlled trial of

fluconazole to prevent fungal infections in patients undergoing bone mar-

row transplantation N Engl J Med 1992 326 845ndash51

70 Slavin MA Osborne B Adams R et al Efficacy and safety of flu-

conazole prophylaxis for fungal infectionsaftermarrow transplantationmdasha

prospective randomized double-blind study J Infect Dis 1995 1711545ndash52

71 Marr KA Seidel K SlavinMA et al Prolonged fluconazole prophy-

laxis is associated with persistent protection against candidiasis-related

death in allogeneic marrow transplant recipients long-term follow-up of a

randomized placebo-controlled trial Blood 2000 96 2055ndash61

72 AlangadenGChandrasekar PH BaileyE et al Antifungal prophy-

laxis with low-dose fluconazole during bone marrow transplantation The

Bone Marrow Transplantation Team Bone Marrow Transplant 1994 14919ndash24

73 Wolff SN Fay J Stevens D et al Fluconazole versus low-dose

amphotericin B for the prevention of fungal infections in patients under-

going bonemarrow transplantation a study of theNorthAmericanMarrow

Transplant Group Bone Marrow Transplant 2000 25 853ndash9

74 Annaloro C Oriana A Tagliaferri E et al Efficacy of different pro-

phylactic antifungal regimens in bone marrow transplantation Haemato-

logica 1995 80 512ndash17

75 Winston DJ Maziarz RT Chandrasekar PH et al Intravenous and

oral itraconazole versus intravenous and oral fluconazole for long-term

antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant

recipients A multicenter randomized trial Ann Intern Med 2003 138705ndash13

76 MarrKACrippaF LeisenringWet al Itraconazoleversus flucona-

zole forpreventionof fungal infections inpatients receivingallogeneicstem

cell transplants Blood 2004 103 1527ndash33

77 MacMillan ML Goodman JL DeFor TE et al Fluconazole to pre-

vent yeast infections in bone marrow transplantation patients a random-

ized trial of high versus reduced dose and determination of the value of

maintenance therapy Am J Med 2002 112 369ndash79

78 Marr KA Seidel K White TC et al Candidemia in allogeneic blood

and marrow transplant recipients evolution of risk factors after the adop-

tion of prophylactic fluconazole J Infect Dis 2000 181 309ndash16

79 van Burik JA Ratanatharathorn V Stepan DE et al Micafungin

versus fluconazole for prophylaxis against invasive fungal infections dur-

ing neutropenia in patients undergoing hematopoietic stem cell trans-

plantation Clin Infect Dis 2004 39 1407ndash16

80 Prentice HG Kibbler CC Prentice AG Towards a targeted risk-

based antifungal strategy in neutropenic patients Br J Haematol 2000

110 273ndash84

81 Laverdiere M Rotstein C Bow EJ et al Impact of fluconazole

prophylaxis on fungal colonizatin and infection rates in neutropenic

patients The Canadian Fluconazole Study J Animicrob Chemother

2000 46 1001ndash8

82 Winston DJ Chandrasekar PH Lazarus HM et al Fluconazole

prophylaxis of fungal infections in patients with acute leukemia Results

of a randomized placebo-controlled double-blind multicenter trial Ann

Intern Med 1993 118 495ndash503

83 Chandrasekar PHGatnyCMEffect of fluconazole prophylaxis on

fever and use of amphotericin in neutropenic cancer patients Bone Mar-

row Transplantation Team Chemotherapy 1994 40 136ndash43

84 Rotstein C Bow EJ Laverdiere M et al Randomized placebo-

controlled trial of fluconazole prophylaxis for neutropenic cancer patients

benefit basedonpurposeand intensity of cytotoxic therapy TheCanadian

Fluconazole Prophylaxis Study Group Clin Infect Dis 1999 28 331ndash40

85 YamacK Senol E HaznedarR Prophylactic use of fluconazole in

neutropenic cancer patients Postgrad Med J 1997 71 284ndash6

86 KernW BehreG Rudolf T et al Failure of fluconazole prophylaxis

to reducemortality or the requirement of systemic amphotericin B therapy

during treatment for refractory acute myeloid leukemia results of a

Review

406

prospective randomized phase III study German AML Cooperative

Group Cancer 1998 83 291ndash301

87 SchaffnerA SchaffnerM Effect of prophylactic fluconazole on the

frequencyof fungal infectionsamphotericinBuseandhealthcarecosts in

patients undergoing intensive chemotherapy for hematologic neoplasias

J Infect Dis 1995 172 1035ndash41

88 Egger T Gratwohl A Tichelli A et al Comparison of fluconazole

with oral polyenes in the prevention of fungal infections in neutropenic

patients A prospective randomized single-center study Support Care

Cancer 1995 3 139ndash46

89 Morgenstern GR Prentice AG Prentice H et al A randomized

controlled trial of itraconazole versus fluconazole for the prevention of

fungal infections in patients with haematological malignancies UK Mul-

ticentre Antifungal Prophylaxis Study Group Br J Haematol 1999 105901ndash11

90 EllisMEClinkHErnstPetalControlledstudyof fluconazole in the

preventionof fungal infections in neutropenic patientswith haematological

malignancies and bone marrow transplant recipients Eur J Clin Microbiol

Infect Dis 1994 13 3ndash11

91 Philpott-Howard JN Wade JJ Mufti GJ et al Randomized com-

parisonoforal fluconazoleversusoralpolyenes for thepreventionof fungal

infection in patients at risk of neutropenia Multicentre Study Group

J Antimicrob Chemother 1993 31 973ndash84

92 Ninane J A multicentre study of fluconazole versus oral polyenes

in the prevention of fungal infection in children with hematological or

oncological malignancies Multicentre Study Group Eur J Clin Microbiol

Infect Dis 1994 13 330ndash7

93 Menichetti F Del Favero A Martino P et al Preventing fungal

infection in neutropenic patients with acute leukemia fluconazole com-

pared with oral amphotericin B The GIMEMA Infection Program Ann

Intern Med 1994 120 913ndash18

94 Akiyama H Mori S Tanikawa S et al Fluconazole versus oral

amphotericin B in preventing fungal infection in chemotherapy-induced

neutropenic patients with haematological malignancies Mycoses 1996

36 373ndash8

95 Meunier F AounM JanssensM et al Chemoprophylaxis of fungal

infections in granulocytopenic patients using fluconazole versus oral

amphotericin B Drug Invest 1991 3 258ndash65

96 Rozenberg-Arska M Dekker AW Branger J et al A randomized

study to compare oral fluconazole to amphotericin B in the prevention of

fungal infections inpatientswithacute leukaemiaJAntimicrobChemother

1991 27 369ndash76

97 Brammer KW Management of fungal infection in neutropenic

patients with fluconazole Haematol Blood Transfus 1990 33 546ndash50

98 Bodey GP Anaissie EJ Elting LS et al Antifungal prophylaxis

during remission induction therapy for acute leukemia fluconazole versus

intravenous amphotericin B Cancer 1994 73 2099ndash106

99 Kanda Y Yamamoto R Chizuka A et al Prophylactic action of

oral fluconazole against fungal infection in neutropenic patients A

meta-analysis of 16 randomized controlled trials Cancer 2000 891611ndash25

100 Bow EJ Laverdiere M Lussier N et al Antifungal prophylaxis for

severely neutropenic chemotherapy recipients a meta analysis of

randomized-controlled clinical trials Cancer 2002 94 3230ndash46

101 Viscoli C Paesmans M Sanz M et al Association between

antifungal prophylaxis and rate of documented bacteremia in febrile

neutropenic cancer patients Clin Infect Dis 2001 32 1532ndash7

102 HughesWT Armstrong D BodeyGP et al 2002 guidelines for the

use of antimicrobial agents in neutropenic patients with cancerClin Infect

Dis 2002 34 730ndash51

103 Cornely OA Bohme A Buchheidt D et al Prophylaxis of invasive

fungal infections in patients with hematological malignancies and solid

tumorsmdashguidelines of the Infectious Diseases Working Party (AGIHO)

of the German Society of Hematology and Oncology (DGHO) Ann

Hematol 2003 82 Suppl 2 186ndash200

104 McNeil MM Nash SL Hajjeh RA et al Trends in mortality due to

invasivemycotic diseases in theUnitedStates 1980ndash1997Clin InfectDis

2001 33 641ndash7

105 KibblerCCSeatonSBarnesRA et alManagement and outcome

of bloodstream infections due to Candida species in England and Wales

J Hosp Infect 2003 54 18ndash24

106 Marchetti O Bille J Fluckiger U et al Fungal Infection Network of

Switzerland Epidemiology of candidemia in Swiss tertiary care hospitals

secular trends 1991-2000 Clin Infect Dis 2004 38 311ndash20

107 Gudlaugsson O Gillespie S Lee K et al Attributable mortality of

nosocomial candidemia revisited Clin Infect Dis 2003 37 1172ndash7

108 Ibanez-Nolla J Nolla-Salas M Leon MA et al Early diagnosis of

candidiasis in nonneutropenic critically ill patients J Infect 2004 48181ndash92

109 BlumbergHMJarvisWRSoucieJMetalRisk factors for candidal

bloodstream infections in surgical intensive care unit patients the NEMIS

prospective multicenter study The National Epidemiology of Mycosis

Survey Clin Infect Dis 2001 33 177ndash86

110 Pittet D Monod M Suter PM et al Candida colonization and

subsequent infections in critically ill surgical patients Ann Surg 1994

220 751ndash8

111 Sendid B Poirot JL Tabouret M et al Combined detection of

mannanaemia and antimannan antibodies as a strategy for the diagnosis

of systemic infectioncausedbypathogenicCandidaspeciesJMedMicro-

biol 2002 51 433ndash42

112 Bar W Hecker H Diagnosis of systemic Candida infections in

patients of the intensive care unit Significance of serum antigens and

antibodies Mycoses 2002 45 22ndash8

113 Calandra T Marchetti O Clinical trials of antifungal prophy-

laxis among patients undergoing surgery Clin Infect Dis 2004 39S185ndash92

114 Sypula WT Kale-Pradhan PB Therapeutic dilemma of flucona-

zole prophylaxis in intensive care Ann Pharmacother 2002 36 155ndash9

115 Pelz RK Hendrix CW Swoboda SM et al Double-blind placebo-

controlled trial of fluconazole to prevent candidal infections in critically ill

surgical patients Ann Surg 2001 233 542ndash8

116 Eggimann P Francioli P Bille J et al Fluconazole prophylaxis

prevents intraabdominal candidiasis in high-risk surgical patients Crit

Care Med 1997 27 1066ndash72

117 Swoboda SM Merz WG Lipsetta PA Candidemia the impact of

antifungal prophylaxis in a surgical intensive care unitSurg Infect20034345ndash54

118 Todd JC OrsquoNeal VG Grady KP et al Reduction of secondary

mycotic infections in the trauma intensivie care unit with fluconazole

J Trauma 1991 31 1722ndash27

119 Jacobs S Price Evans DA Tariq M et al Fluconazole improves

survival in septic shock a randomized double-blind prospective studyCrit

Care Med 2003 31 1938ndash46

120 Zervos EE Fink GW Norman JG et al Fluconazole increases

bactericidal activity of neutrophils through non-cytokine-mediated path-

way J Trauma 1996 41 465ndash70

121 AblesAZBlumerNAValainisGTetal Fluconazoleprophylaxis of

severe Candida infection in trauma and postsurgical patients a prospec-

tive double-blind randomised placebo-controlled trial Infect Dis Clin

Pract 2000 9 169ndash75

122 Kam LW Lin JD Management of systemic candidal infections in

the intensive care unit Am J Health Syst Pharm 2002 59 33ndash41

123 Rocco TR Reinert SE Simms HH Effects of fluconazole admin-

istration in critically ill patients analysis of bacterial and fungal resistance

Arch Surg 2000 135 160ndash5

124 Tortorano AM Caspani L Rigoni AL et al Candidosis in the inten-

sive care unit a 20-year survey J Hosp Infect 2004 57 8ndash13

125 EggimannPGarbino J Pittet DManagement ofCandida species

infections in critically ill patients Lancet Infect Dis 2003 3 772ndash85

Review

407

126 EggimannPGarbinoJPittetDEpidemiologyofCandida species

infections incritically ill non-immunosuppressedpatientsLancet InfectDis

2003 3 685ndash702

127 Martins MD Lozano-Chiu M Rex JH Declining rates of oropha-

ryngeal candidiasis and carriage of Candida albicans associated with

trends toward reduced rates of carriage of fluconazole-resistant C albi-

cans in human immunodeficiency virus-infected patients Clin Infect Dis

1998 27 1291ndash4

128 Powderly WG Finkelstein D Feinberg J et al A randomized trial

comparing fluconazole with clotrimazole troches for the prevention of fun-

gal infections in patients with advanced human immunodeficiency virus

infection NIAID AIDS Clinical Trials Group N Engl J Med 1995 332700ndash5

129 Leen CL Dunbar EM Ellis ME et al Once-weekly fluconazole to

prevent recurrenceof oropharyngeal candidiasis inpatientswithAIDSand

AIDS-related complex a double-blind placebo-controlled study J Infect

1990 21 55ndash60

130 Stevens DA Greene SI Lang OS Thrush can be prevented in

patients with acquired immunodeficiency syndrome and the acquired

immunodeficiency syndrome-related complex Randomized double-

blind placebo-controlled study of 100-mg oral fluconazole daily Arch

Intern Med 1991 151 2458ndash64

131 Just-Nubling G Gentschew G Meissner K Fluconazole prophy-

laxis of recurrent oral candidiasis inHIV-positive patientsEur JClinMicro-

biol Infect Dis 1991 10 917ndash21

132 Marriott DJ Jones PD Hoy JF et al Fluconazole once a week as

secondary prophylaxis against oropharyngeal candidiasis in HIV-infected

patients A double-blind placebo-controlled studyMed J Aust 1993 158312ndash16

133 Schuman P Capps L Peng G et al Weekly fluconazole for the

prevention ofmucosal candidiasis inwomenwithHIV infection A random-

ized double-blind placebo-controlled trial Terry Beirn Community Pro-

grams for Clinical Research on AIDSAnn InternMed 1997 126 689ndash96

134 Havlir DV DubeMPMcCutchan JA et al Prophylaxis with weekly

versus daily fluconazole for fungal infections in patients with AIDS Clin

Infect Dis 1998 27 1369ndash75

135 Pagani JL Chave JP Casjka C et al Efficacy tolerability and

development of resistance in HIV-positive patients treated with flucona-

zole for secondary prevention of oropharyngeal candidiasis a random-

ized double-blind placebo-controlled trial JAntimicrobChemother 2002

50 231ndash40

136 Vazquez JA Peng G Sobel JD et al Evolution of antifungal sus-

ceptibility amongCandidaspecies isolates recovered fromhuman immun-

odeficiency virus-infected women receiving fluconazole prophylaxis Clin

Infect Dis 2001 33 1069ndash75

137 Delfraissy JF Prise en charge therapeutique des patients infectespas le VIH Rapport Delfraissy Paris Flammarion 2004

138 DePauwBERaemaekers JMDonnelly JPet al Anopenstudyon

the safety and efficacy of fluconazole in the treatment of disseminated

Candida infections in patients treated for hematological malignancy Ann

Hematol 1995 70 83ndash7

139 Anaissie EJ Vartivarian SE Abi-Said D et al Fluconazole versus

amphotericin B in the treatment of hematogenous candidiasis a matched

cohort study Am J Med 1996 101 170ndash6

140 Anaissie EJ Darouiche RO Abi-Said D et al Management of

invasive candidal infections results of a prospective randomized multi-

center study of fluconazole versus amphotericin B and review of the

literature Clin Infect Dis 1996 23 964ndash72

141 Myoken Y Kyo T Kohara T et al Breakthrough fungemia caused

by azole-resistant Candida albicans in neutropenic patients with acute

leukemia Clin Infect Dis 2003 36 1496ndash7

142 Anttila VJ FarkkilaM JanssonSE et al Diagnostic laparoscopy in

patientswith acute leukemiaandsuspectedhepatic candidiasisEur JClin

Microbiol Infect Dis 1997 16 637ndash43

143 Anaissie E Bodey GP Kantarjian H et al Fluconazole therapy for

chronic disseminated candidiasis in patients with leukemia and prior

amphotericin B therapy Am J Med 1991 91 142ndash50

144 KauffmanCA BradleySFRossSC et al Hepatosplenic candidia-

sis successful treatment with fluconazole Am J Med 1991 91 137ndash41

145 Kontoyiannis DP Luna MA Samuels BI et al Hepatosplenic can-

didiasis A manifestation of chronic disseminated candidiasis Infect Dis

Clin North Am 2000 14 721ndash39

146 Graninger W Presteril E Schneeweiss B et al Treatment of

Candida albicans fungaemia with fluconazole J Infect 1993 26 133ndash46

147 Phillips P Shafran S Garber G et al Multicenter randomized trial

of fluconazole versus amphotericin B for treatment of candidemia in

non-neutropenic patients Canadian Candidemia Study Group Eur J

Clin Microbiol Infect Dis 1997 16 337ndash45

148 Rex JH Bennett JE Sugar AM et alA randomized trial comparing

fluconazolewithamphotericinB for the treatmentof candidemia inpatients

without neutropenia Candidemia Study Group and the National Institute

N Engl J Med 1994 331 1325ndash30

149 Abele-Horn M Kopp A Sternberg U et al A randomized study

comparing fluconazolewith amphotericinB5-flucytosine for the treatment

of systemic Candida infections in intensive care patients Infection 1996

24 426ndash32

150 Nguyen MH Peacock JE Jr Tanner DC et al Therapeutic

approaches in patients with candidemia Evaluation in a multicenter

prospective observational study Arch Intern Med 1995 155 2429ndash35

151 Rex JH Pappas PG Karchmer AW et al A randomized and

blinded multicenter trial of high-dose fluconazole plus placebo versus flu-

conazole plus amphotericin B as therapy for candidemia and its con-

sequences in non-neutropenic subjectsClin Infect Dis 2003 36 1221ndash8

152 Mora-Duarte J Betts R Rotstein C et al Comparison of

caspofungin and amphotericin B for invasive candidiasis N Engl J Med

2002 347 2020ndash9

153 Sugar AM Saunders C Diamond RD et al Successful treatment

of Candida osteomyelitis with fluconazole A noncomparative study of

two patients Diagn Microbiol Infect Dis 1990 13 517ndash20

154 Tang C Successful treatment of Candida albicans osteomyelitis

with fluconazole J Infect 1993 26 89ndash92

155 LafontAOliveAGelmanMet alCandidaalbicansspondylodisci-

tis and vertebral osteomyelitis in patients with intravenous heroin drug

addiction Report of 3 new cases J Rheumatol 1994 21 953ndash6

156 Hennequin C Bouree P Hiesse C et al Spondylodiskitis due to

Candida albicans report of two patients who were successfully treated

with fluconazole and review of the literature Clin Infect Dis 1996 23176ndash8

157 Jonnalagadda S VeerabaguMP Rakela J et alCandida albicans

osteomyelitis in a liver transplant recipient a case report and review of the

literature Transplantation 1996 62 1182ndash4

158 Rossel P Schonheyder HC Nielsen H Fluconazole therapy

inCandidaalbicansspondylodiscitisScandJ InfectDis199830 527ndash30

159 TurnerDLJohnsonSARuleSASuccessful treatmentof candidal

osteomyelitis with fluconazole following failure with liposomal ampho-

tericin B J Infect 1999 38 51ndash3

160 El-Zaatari MM Hulten K Fares Y et al Successful treatment of

Candida albicans osteomyelitis of the spine with fluconazole and surgical

debridement case report J Chemother 2002 14 627ndash30

161 Seravalli L Van Linthoudt D Bernet C et al Candida glabrata

spinal osteomyelitis involving two contiguous lumbar vertebrae a case

report and review of the literature Diagn Microbiol Infect Dis 2003 45137ndash41

162 Garbino J Schnyder I LewDP et al An unusual cause of vertebral

osteomyelitis Candida species Scand J Infect Dis 2003 35 288ndash91

163 TunkelARThomasCYWispelweyBCandidaprostheticarthritis

report of a case treated with fluconazole and review of the literature Am J

Med 1993 94 100ndash3

Review

408

164 CushingRD FulgenziWR Synovial fluid levels of fluconazole in a

patient with Candida parapsilosis prosthetic joint infection who had an

excellent clinical response J Arthroplasty 1997 12 950

165 Fukasawa N Shirakura K Candida arthritis after total knee

arthroplastymdasha case of successful treatment without prosthesis removal

Acta Orthop Scand 1997 68 306ndash7

166 Lerch K Kalteis T Schubert T et al Prosthetic joint infections with

osteomyelitis due to Candida albicans Mycoses 2003 46 462ndash6

167 Clancy CJ Nguyen MH Morris AJ Candidal mediastinitis an

emerging clinical entity Clin Infect Dis 1997 25 608ndash13

168 PetrikkosGSkiadaA SabatakouH et al Case report Successful

treatment of two cases of post-surgical sternal osteomyelitis due to

Candida krusei and Candida albicans respectively with high doses of

triazoles (fluconazole itraconazole) Mycoses 2001 44 422ndash5

169 Weers-Pothoff GHavermans JF Kamphuis J et alCandida tropi-

calis arthritis in a patient with acutemyeloid leukemia successfully treated

with fluconazole case report and review of the literature Infection 1997

25 109ndash11

170 Laatikainen L TuominenM vonDickhoff K Treatment of endoge-

nous fungal endophthalmitis with systemic fluconazole with or without

vitrectomy Am J Ophthalmol 1992 113 205ndash7

171 Borne MJ Elliott JH OrsquoDay DM Ocular fluconazole treatment of

Candidaparapsilosisendophthalmitis after failed intravitreal amphotericin

B Arch Ophthalmol 1993 111 1326ndash7

172 Zarbin MA Becker E Witcher J et al Treatment of presumed

fungal endophthalmitis with oral fluconazole Ophthalmic Surg Lasers

1996 27 628ndash31

173 WongVK TasmanWEagleRC et al BilateralCandida parapsilo-

sis endophthalmitis Arch Ophthalmol 1997 115 670ndash2

174 Kauffman CA Bradley SF Vine AK Candida endophthalmitis

associated with intraocular lens implantation efficacy of fluconazole ther-

apy Mycoses 1993 36 13ndash17

175 del Palacio A Cuetara MS Ferro M et al Fluconazole in the man-

agement of endophthalmitis in disseminated candidosis of heroin addicts

Mycoses 1993 36 193ndash9

176 Luttrull JK Wan WL Kubak BM et al Treatment of ocular fungal

infections with oral fluconazole Am J Ophthalmol 1995 119 477ndash81

177 Akler ME Vellend H McNeely DM et al Use of fluconazole in the

treatment of candidal endophthalmitis Clin Infect Dis 1995 20 657ndash64

178 Christmas NJ Smiddy WE Vitrectomy and systemic fluconazole

for treatment of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1996 27 1012ndash18

179 EssmanTFFlynnHWSmiddyWEet al Treatment outcomes in a

10-year study of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1997 28 185ndash94

180 Martinez-Vazquez C Fernandez-Ulloa J Bordon J et al Candida

albicans endophthalmitis in brown heroin addicts response to early vit-

rectomyprecededand followedbyantifungal therapyClin InfectDis1998

27 1130ndash3

181 Aleixo MJ Caldeira L Ferreira ML Candida albicans meningitis

clinical case J Infect 2000 40 191ndash2

182 InoueY YozuR Ueda T et al A case report ofCandida parapsilo-

sis endocarditis J Heart Valve Dis 1998 7 240ndash2

183 Isalska BJ Stanbridge TN Fluconazole in the treatment of candi-

dal prosthetic valve endocarditis BMJ 1988 297 178ndash9

184 Martino P Meloni G Cassone A Candidal endocarditis and treat-

ment with fluconazole and granulocyte-macrophage colony-stimulating

factor Ann Intern Med 1990 112 966ndash7

185 Roupie E Darmon JY Brochard L et al Fluconazole therapy of

candidal native valveendocarditisEur JClinMicrobiol InfectDis199110458ndash9

186 Hernandez JA Gonzalez-Moreno M Llibre JM et al Candidal

mitral endocarditis and long-term treatment with fluconazole in a patient

with human immunodeficiency virus infection Clin Infect Dis 1992 151062ndash3

187 Venditti MDeBernardis FMicozzi A et al Fluconazole treatment

of catheter-related right-sided endocarditis caused by Candida albicans

and associated with endophthalmitis and folliculitis Clin Infect Dis 1992

14 422ndash6

188 Wallbridge DR McCartney AC Richardson MD Fluconazole in

the treatment ofCandidaprosthetic valveendocarditisMycoses199336259ndash61

189 Otaki M Kitamura N Candida prosthetic valve endocarditis An

autopsy review Int Surg 1993 78 252ndash3

190 Czwerwiec FS Bilsker MS Kamerman ML et al Long-term sur-

vival after fluconazole therapy of candidal prosthetic valve endocarditis

Am J Med 1993 94 545ndash6

191 Thakur RK Skelcy KM Kahn RN et al Successful treatment of

Candida prosthetic valve endocarditis with a combination of fluconazole

and amphotericin B Crit Care Med 1994 22 712ndash14

192 Cancelas JA Lopez JCabezudoE et al Native valve endocarditis

due toCandida parapsilosis a late complication after bonemarrow trans-

plantation-related fungemia Bone Marrow Transplant 1994 13 333ndash4

193 Zahid MA Klotz SA Hinthorn DR Medical treatment of recurrent

candidemia in a patient with probable Candida parapsilosis prosthetic

valve endocarditis Chest 1994 105 1597ndash8

194 Wells CJ Leech G Lever AM et al Treatment of native valve

Candida endocarditis with fluconazole J Infect 1995 31 233ndash5

195 Gilbert HM Peters ED Lang SJ et al Successful treatment of

fungal prosthetic valve endocarditis case report and review Clin Infect

Dis 1996 22 348ndash54

196 Nguyen MH Nguyen ML Yu VL et al Candida prosthetic valve

endocarditis prospective study of six cases and review of the literature

Clin Infect Dis 1996 22 262ndash7

197 Lejko-Zupanc T Kozelj M A case of recurrent Candida parapsilo-

sis prosthetic valve endocarditis cure bymedical treatment alone J Infect

1997 35 81ndash2

198 Joly V BelmatougN Leperre A et al Pacemaker endocarditis due

to Candida albicans case report and review Clin Infect Dis 1997 251359ndash62

199 Rex JH Walsh T Sobel JD et al Practice guidelines for the treat-

mentof candidiasis InfectiousDiseasesSocietyofAmericaClin InfectDis

2000 30 662ndash78

200 Baddour LM Long-term suppressive therapy for Candida para-

psilosis-induced prosthetic valve endocarditis Mayo Clin Proc 1995

70 773ndash5

201 Melgar GR Nasser RM Gordon SM Fungal prosthetic valve

endocarditis in 16 patients An 11-year experience in a tertiary care hos-

pital Medicine 1997 76 94ndash103

202 Dupont H Paugam-Burtz C Muller-Serieys C et al Predictive

factors of mortality due to polymicrobial peritonitis with Candida isolation

in peritoneal fluid in critically ill patients Arch Surg 2002 137 1341ndash6

203 Lee SC FungCP ChenHY et alCandida peritonitis due to peptic

ulcer perforation incidence rate risk factors prognosis and susceptibility

to fluconazole and amphotericin B Diagn Microbiol Infect Dis 2002 4423ndash7

204 Levine J Bernard DB Idelson BA et al Fungal peritonitis compli-

cating continuous ambulatory peritoneal dialysis successful treatment

with fluconazole a new orally active antifungal agent Am J Med 1989

86 825ndash7

205 Michel C Courdavault L al Khayat R et al Fungal peritonitis in

patients on peritoneal dialysis Am J Nephrol 1994 14 113ndash20

206 WangAYYuAWLi PKet al Factors predicting outcomeof fungal

peritonitis in peritoneal dialysis analysis of a 9-year experience of fungal

peritonitis in a single center Am J Kidney Dis 2000 36 1183ndash92

207 Hawkins JL Baddour LM Candida lusitaniae infections in the era

of fluconazole availability Clin Infect Dis 2003 36 14ndash18

Review

409

208 KauffmanCAVazquezJASobel JDetal Prospectivemulticenter

surveillance study of funguria in hospitalized patients The National Insti-

tute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group

Clin Infect Dis 2000 30 14ndash18

209 Sobel JD Kauffman CA McKinsey D et al Candiduria a random-

ized double-blind study of treatment with fluconazole and placebo The

National Institute of Allergy and Infectious Diseases (NIAID) Mycoses

Study Group Clin Infect Dis 2000 30 19ndash24

210 LundstromTSobel JNosocomial candiduria a reviewClin Infect

Dis 2001 32 1602ndash7

211 Kaufman D Boyle R Hazen KC et al Fluconazole prophylaxis

against fungal colonization and infection in preterm infants N Engl J

Med 2001 345 1660ndash6

212 Kicklighter SD Springer SC Cox T et al Fluconazole for the pro-

phylaxis against candidal rectal colonization in the very low birth weight

infant Pediatrics 2001 107 293ndash8

213 McGuire W Clerihew L Austin N Prophylactic intravenous anti-

fungal agents to prevent mortality and morbidity in very low birth weight

infants Cochrane Database Syst Rev 2004 CD003850

214 Agarwal JBansalSMalikGKetal Trends inneonatal septicemia

emergence of non-albicans Candida Indian Pediatr 2004 41 712ndash15

215 FasanoCOrsquoKeefe JGibbsD Fluconazole treatment of neonates

and infants with severe fungal infections not treatable with conventional

agents Eur J Clin Microbiol Infect Dis 1994 13 351ndash4

216 Wainer S Cooper PA Gouws H et al Prospective study of flu-

conazole therapy in systemicneonatal fungal infectionPediatr InfectDis J

1997 16 763ndash7

217 Huang YC Lin TY Lien RI et al Fluconazole therapy in neonatal

candidemia Am J Perinatol 2000 17 411ndash15

218 Huttova M Hartmanova I Kralinsky K et al Candida fungemia in

neonates treated with fluconazole report of forty cases including eight

with meningitis Pediatr Infect Dis J 1998 17 1012ndash15

219 Gurpinar AN Balkan E Kilic N et al Fluconazole treatment of

neonates and infants with severe fungal infections J Int Med Res 1997

25 214ndash18

220 Driessen M Ellis JB Muwazi F et al The treatment of systemic

candidiasis in neonates with oral fluconazole Ann Trop Pediatr 1997 17263ndash71

221 Driessen M Ellis JB Cooper PA et al Fluconazole vs

amphotericin B for the treatment of neonatal fungal septicemia

a prospective randomized trial Pediatr Infect Dis J 1997 151107ndash12

222 Marr B Gross S Cunningham C et al Candidal sepsis and

meningitis in a very-low-birth-weight infant successfully treated with flu-

conazole and flucytosine Clin Infect Dis 1994 19 795ndash6

223 Oleinik EM Della-Latta P Rinaldi MG et al Candida lusitaniae

osteomyelitis in a premature infant Am J Perinatol 1993 10 313ndash15

224 Mondal RK Singhi SC Chakrabarti A Randomized comparison

between fluconazole and itraconazole for the treatment of candidemia in a

pediatric intensive care unit a preliminary study Pediatr Crit Care Med

2004 5 561ndash5

225 Viscoli C Castagnola E Fioredda F et al Fluconazole in the treat-

ment of candidiasis in immunocompromised children Antimicrob Agents

Chemother 1991 35 365ndash7

226 Decruyenaere J Colardyn F Vogelaers D et al Combined use of

fluconazole and selective digestive decontamination in the prevention of

fungal infection after adult liver transplantation Transplant Proc 1995 273515ndash16

227 Koh LP Kurup A Goh YT et al Randomized trial of fluconazole

versus low-dose amphotericin B in prophylaxis against fungal infections in

patients undergoing hematopoietic stem cell transplantationAmJHema-

tol 2002 71 260ndash7

228 Gluckman E Esperou-Bourdeau H Ribaud P et al Comparaison

entre le fluconazole et le ketoconazole pour la prophylaxie des infections

fongiques chez les patients traites par greffe de moelle allogenique Cah

Oncol 1993 2 167ndash9

Review

410

clinical cases reported the efficacy of fluconazole alone or incombination with other treatments in cases of endophthalmitisdue to Candida spp16170ndash173 Finally several recent series con-firmed fluconazole efficacy in cases of severe ocular infectionsdue to susceptible Candida sp in non-neutropenic patients174ndash180

Their results are summarized in Table 13 Most cases are due toC albicans and fluconazole-resistant species causing endoph-thalmitis is extremely rare On the basis of these data the IDSArecommends the use of fluconazole in this indication particularlyas follow-up therapy58

Meningitis due to Candida sp

Very few data exist on fluconazolersquos efficacy for the initial treat-ment of Candida sp meningitis in adults although this drug has avery good CSF penetration Oral fluconazole (800 mgday for3 months then 200 mgday) was successful for the treatment ofa C albicans meningitis in an HIV-infected patient with a CD4 cellcount of 35 cellsmm3 who refused intravenous therapy181

Endocarditis due to Candida sp

No series has documented the efficacy of fluconazole in endocard-itis due to Candida sp Only a few clinical cases have been pub-lished and most of these are summarized in Table 14182ndash198 Thesecases illustrate the efficacy of fluconazole (sometimes with nosurgical treatment) in endocarditis due to C albicans and alsoin endocarditis related to some non-albicans Candida spp espe-cially C parapsilosis However no study has demonstrated thesuperiority of fluconazole over amphotericin B in this indicationand there are insufficient data to recommend fluconazole as the firstline treatment for endocarditis due to Candida spp58199 Theechinocandins might have a place as primary therapy in thesecases Fluconazole (200ndash400 mgday) is often employed as partof a long-term suppressive regimen especially if valve replacementis not possible because of the high propensity for delayed relapse ofcandidal endocarditis200201

Peritonitis due to Candida sp

Peritonitis due to Candida sp may develop in patients with peri-toneal dialysis catheters or in those with surgical or traumaticinjury to the gut wall In this latter situation Candida spp areusually part of a polymicrobial infection Isolation of Candidaby direct examination of peritoneal fluid is an independent factorfor a severe outcome202 and recent small studies suggest thatprompt effective adequate and safe antifungal therapy shouldbe given in all cases of Candida sp peritonitis in order to lowerthe mortality rate and shorten the hospital stay113116 In a recentstudy of 23 cases secondary to peptic ulcer perforation the mor-tality rate in patients receiving fluconazole (200 mg intravenouslytwice daily for 2ndash4 weeks) was high (five of eight cases) probablyrelated to inadequate or too late initiation of antifungal therapy203

Some cases showing fluconazole efficacy have been reported inpatients with continuous ambulatory peritoneal dialysis eitheralone or in combination with flucytosine204ndash207 Catheter removalis crucial in these cases

Urinary infections due to Candida spp

Candida is by far the most frequent agent of urinary fungal infec-tions The line between colonization and real infection is generallyblurred Candiduria usually present as nosocomial infections T

able

13

Rep

ort

so

fp

atie

nts

wit

hen

do

ph

thal

mit

isd

ue

toCandida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Met

ho

do

log

y

of

stu

dy

Candida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Do

seo

f

flu

con

azo

le(m

gd

ay)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y

(fo

llo

w-u

pd

ura

tio

n)

Mar

tin

ez-V

azq

uez

etal

18

0p

rosp

ecti

ve

Calbicans

11

40

02

ndash8

wee

ks

AM

Biv

(n=

9)

or

no

trea

tmen

t(n

=1

)u

nti

l

vit

rect

om

y(n

=1

0

2ndash

18

0

day

saf

ter

dia

gn

osi

s)

91

1(6

mo

nth

s)

Ess

man

etal

17

9re

tro

spec

tiv

eCalbicansCtropicalis

5u

nsp

ecif

ied

un

spec

ifie

dv

itre

cto

myndash

loca

lA

MB

55

(25

ndash1

15

mo

nth

s)

Ch

rist

mas

etal

17

8p

rosp

ecti

ve

CalbicansCtropicalis

51

00

ndash2

00

3ndash

6w

eek

sv

itre

cto

my

55

(4ndash

11

mo

nth

s)

Ak

leret

al

17

7re

tro

spec

tiv

eu

nsp

ecif

ied

6to

tal

med

ian

do

se

=9

97

5m

g

med

ian

=5

2d

ays

AM

Biv

lt5

00

mg

+

vit

rect

om

y

1

56

re

lap

se

1(pound

6w

eek

s)

Lu

ttru

llet

al

17

6re

tro

spec

tiv

eCalbicans

(n=

2)

un

spec

ifie

d(n

=2

)

42

00

ndash4

00

4w

eek

s(n

=3

)v

itre

cto

my

1

44

(3ndash

25

mo

nth

sn

=3

)

del

Pal

acio

etal

17

5re

tro

spec

tiv

eCalbicans

74

00

(1d

ay)

then

20

03

wee

ks

ndash6

7(v

itre

cto

my

refu

sal

in

1p

atie

nt)

(Dagger6

mo

nth

s)

Kau

ffm

anet

al

17

4re

tro

spec

tiv

e

len

sim

pla

nts

Cparapsilosis

44

00

(20

0in

pat

ien

ts

wit

hre

nal

fail

ure

)

1y

ear

fail

ure

of

loca

lA

MB

rela

pse

ifn

ole

ns

abla

tio

n

(2y

ears

afte

rst

op

pin

g)

AM

B

amphote

rici

nB

iv

in

trav

enous

Review

401

Table

14

Rep

ort

so

fp

atie

nts

wit

hen

do

card

itis

du

eto

Candida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Val

vu

lar

inv

olv

emen

tCandida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Dose

of

fluco

naz

ole

(mg

day

)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y(f

oll

ow

-up

du

rati

on

)

Ino

ueet

al

18

2ao

rtic

val

ve

Cparapsilosis

16

00

then

40

01

8m

on

ths

surg

ery

reco

ver

y(1

8m

on

ths)

Lej

ko

-Zu

pan

cet

al

19

7m

itra

lp

rost

hes

isCparapsilosis

14

00

(14

day

s)th

en1

00

8m

on

ths

AM

B(3

9g

)A

BC

D

(15

g)

no

rep

lace

men

t

reco

ver

y(gt

3y

ears

)

Joly

etal

19

8p

acem

aker

Calbicans

14

00

(6d

ays)

then

20

07

mo

nth

ssu

rger

yre

cov

ery

(18

mo

nth

s)

Ng

uy

enet

al

19

6ao

rtic

pro

sth

esis

Calbicans

14

00

then

20

04

5y

ears

AM

B+

5F

C

12

wee

ks

no

rep

lace

men

t

reco

ver

y(5

5y

ears

)

Gil

ber

tet

al

19

5ao

rtic

pro

sth

esis

Calbicans

12

00

8m

on

ths

surg

ery

AM

B(2

g)

+

5F

C

40

day

s

reco

ver

y(9

mo

nth

s)

Wel

lset

al

19

4m

itra

lan

dtr

icu

spid

val

ves

Calbicans

12

00

ndash4

00

(14

day

s)

then

40

0th

en5

0

65

mo

nth

s

(40

0m

g)

and

10

mo

nth

s

(50

mg

)

no

rep

lace

men

tre

cov

ery

(45

yea

rs)

Zah

idet

al

19

3m

itra

lv

alv

e

(pro

bab

le)

Cparapsilosis

14

00

18

mo

nth

sA

MB

(5g

)+

5F

C

ket

oco

naz

ole

(80

0m

gd

ay

4m

on

ths)

no

rep

lace

men

t

reco

ver

y(5

yea

rs)

Can

cela

set

al

19

2m

itra

lv

alv

eCparapsilosis

12

00

4m

on

ths

surg

ery

A

MB

(2g

)re

cov

ery

(4m

on

ths)

Th

aku

ret

al

19

1ao

rtic

pro

sth

esis

Calbicans

12

00

6w

eek

sA

MB

(30

mg

day

)

6w

eeks

no

repla

cem

ent

reco

ver

y(2

6m

on

ths)

Czw

erw

iecet

al

19

0ao

rtic

pro

sth

esis

Cparapsilosis

14

00

26

mo

nth

sA

MB

(72

5m

g)

no

rep

lace

men

t

reco

ver

y(2

6m

on

ths)

Ota

kiet

al

18

9m

itra

lp

rost

hes

isCparapsilosis

1u

nsp

ecif

ied

68

day

sn

ore

pla

cem

ent

fail

ure

(dea

thd

ue

toce

reb

ral

hae

mo

rrh

age

and

fev

er)

Wal

lbri

dg

eet

al

18

8m

itra

lp

rost

hes

isCparapsilosis

12

00

-40

0gt

7w

eek

sA

MB

(30

0m

g)

no

rep

lace

men

t

reco

ver

y(6

mo

nth

s)

Ven

dit

tiet

al

18

7in

tera

tria

lse

ptu

mCalbicans

12

00

(28

day

s)th

en6

00

(11

day

s)th

en4

00

6m

on

ths

no

rep

lace

men

tre

cov

ery

(14

mo

nth

s)

Her

nan

dez

etal

18

6m

itra

lv

alv

eCalbicans

12

00

3m

on

ths

AM

Bfa

ilu

ren

o

rep

lace

men

t

imp

rov

emen

t(3

mo

nth

s)

Ro

up

ieet

al

18

5ao

rtic

val

ve

Ctropicalis

14

00

50

day

sn

ore

pla

cem

ent

reco

ver

y(1

1m

on

ths)

Mar

tin

oet

al

18

4in

tera

tria

lse

ptu

mCparapsilosis

13

mg

kg

(7d

ays)

then

6m

gk

g

gt3

mo

nth

sG

M-C

SF

(gt6

wee

ks)

no

rep

lace

men

t

reco

ver

y(5

mo

nth

s)

Isal

skaet

al

18

3m

itra

lp

rost

hes

isCparapsilosis

11

00

ndash2

00

11

mo

nth

sn

ore

pla

cem

ent

reco

ver

y(1

yea

r)

AM

B

amph

ote

rici

nB

5

FC

fl

ucy

tosi

ne

AB

CD

am

ph

ote

rici

nB

coll

oid

ald

isp

ersi

on

G

M-C

SF

g

ran

ulo

cyte

ndashm

on

ocy

teco

lon

y-s

tim

ula

tin

gfa

cto

r

Review

402

favoured by indwelling urinary catheters immunosuppressivedrugs or antibiotic prescriptions diabetes mellitus and extremeages C albicans is involved in half of the cases followed byC glabrata in 15 of the cases In 10 of cases infection involvesmore than one species208 Fluconazole achieves a 10 times higherconcentration in urine than in blood with powerful effect even onCglabrata infections Therefore it represents a first line treatment ofany Candida urinary tract infection

In a randomized placebo-controlled multicentre study amongpatients with asymptomatic candiduria Sobel et al209 found thatfluconazole (200 mgday) hastened the time to negative resultsof urine cultures However the rate of negative urine cultures2 weeks after the end of therapy was similar in the fluconazole-and placebo-treated groups showing the minimal utility of treat-ment in that setting Indeed asymptomatic candiduria should betreated only in high-risk situations namely patients with neutrope-nia infants with low birth weight patients with renal allografts andpatients who will undergo urologic manipulations (recommenda-tion of grade B-III from the IDSA) The optimal regimen in thatsetting is not known Short courses regimen are not recommendedand therapy for 1ndash2 weeks should be efficient

Ascending pyelonephritis treatment should also include ade-quate urinary drainage and removal of obstructive fungusballs210 Urinary tract devices should be optimally removed orat least replaced

Haematogenous renal involvement should be treated with high-dose parenteral fluconazole (6 mgkgday) in accordance with therecently published IDSA guidelines57

Fluconazole in childreninfants

No specific approval of fluconazole has been obtained inyoung children before the age of 6 months but a few studieshave evaluated its use in several settings

Prophylaxis of systemic candidiasis in neonates

Few studies have focused on the use of fluconazole as a prophy-lactic agent against invasive candidiasis in neonates Kaufmanet al211 demonstrated in 2001 the efficacy and safety of flucona-zole (3 mgkg every 3 days during the first 2 weeks then every2 days during the following 2 weeks and then every day until thesixth week of life) in extremely low birth weight and high-riskinfants (lt1000 g) in preventing both colonization and invasivefungal infection High risk was defined as the presence of a centralvascular catheter or endotracheal tube Indeed among the 50infants randomly assigned to fluconazole the rate of colonization(22) was significantly lower than in the 50 placebo-treated ones(60) no invasive fungal infection developed in the fluconazolegroup compared with a 20 rate of infection in the placebo groupNo adverse effect of fluconazole was documented

Kicklighter et al212 similarly observed the safety of fluconazoleat 6 mgkg (for 6 weeks) and its efficacy among neonates with lowbirth weight (lt1500 g) in the prevention of rectal colonization(however occurrence of invasive candidiasis was similar inboth groups) A Cochrane review of fluconazole prophylaxis inpreterm infants demonstrated a reduced risk of invasive infection(related risk 020) and mortality (related risk 044) in fluconazole-treated patients compared with placebo-treated patients213

Although concerns about resistance to azoles have been raised

the vast majority ofCandida spp strains have remained susceptibleto fluconazole over the past decade in this population40

Fluconazole in systemic candidiasis in childreninfants

Neonatal candidaemia Candidaemia is a major cause of sepsis inneonatal ICU representing up to 16 of all sepsis cases Therelated mortality rate is high often nearly 50214 Most casesare related to C albicans and C parapsilosis with a recent risein cases related to C tropicalis The main risk factors for invasivecandidiasis among neonates are low birth weight intravascularcatheters intratracheal intubation total parenteral nutrition andadministration of intralipid solution and recent administration ofbroad-spectrum antibiotics and corticosteroids10

Treatment with amphotericin B and 5-flucytosine has been thegold standard for years However amphotericin B has some seriousside effects which makes it mandatory to consider its use in thatsetting With good profile of tolerance good diffusion in all tissuesand body fluids and reliable oral absorption fluconazole has beenstudied as an alternative (see Table 15) In 1994 Fasano et al215

reported the compassionate use of fluconazole among 40 new-borns including 11 who presented with Candida sp meningitisThey were treated with a mean daily dosage of 5 mgkgday for amean duration of 26 days Of the 32 patients with evaluable out-come 31 experienced clearance of infection Other studies haveconfirmed these results in the recent years11216ndash220 In a multicen-tre prospective randomized study Driessen et al220 compared theefficacy and safety of either amphotericin B ndash 5-flucytosine orfluconazole (oral or intravenous dose of 10 mgkg as initialdose and then 5 mgkgday) in neonates with candidaemia Inthe fluconazole group 812 (67) survived versus 611 (55) inthe other group220 Among the four patients who died in the flu-conazole group two had treatment failure versus one in the ampho-tericin B group Cytolytic hepatitis was less frequent in thefluconazole-treated group Two isolated case reports also suggestthat the association of fluconazole and flucytosine might be syn-ergistic in the treatment of neonatal candidaemia222223

Very recently Mondal et al229 compared the efficacy and safetyof oral itraconazole versus oral fluconazole (both doses of 10 mgkgday) in newborns and paediatric patients with candidaemiaSimilar cure rate (81 and 82) mortality rate (95 and 135)and number of side effects were observed224 Fluconazole thusappears as a safe and effective systemic antifungal agent in thesetting of neonatal candidiasis

Children with systemic candidiasis Excluding the setting of neo-natal candidiasis very few studies have however focused on thepaediatric population when studying the efficiency of fluconazolefor the treatment of invasive candidiasis

In 1991 Viscoli et al reported the outcome of 24 immunocom-promised children treated with fluconazole (6 mgkgday) for 34episodes of proven invasive candidiasis A total of 3034 clinicaland microbiological cures were achieved Two patients with fun-gaemia due toC parapsilosis required an increase in dosage of up to12 mgkg Transient drug-related increases of liver transaminasesoccurred in two cases (6)225 In 1994 Fasano et al reported theoutcome of 63 children with AIDS cancer or transplantationprospectively receiving fluconazole as compassionate treatment(dose regimen ranging from 016 to 11 mgkgday mean 34 mgkgday)215 Half of them had fungaemia while the others hadrespiratory urinary tract or superficial oropharyngeal infections

Review

403

Clinical cure or improvement was achieved in 5263 (83) andpathogen eradication was achieved in 4359 (73)17 Huttovaet al218 reported in 1998 the outcome of 10 children withnosocomial fungal meningitis including 8 cases of candidal men-ingitis treated using fluconazole Five of them survived with clinicaland microbiological cure

Conclusions

Almost 15 years after its launch fluconazole remains a cornerstoneof antifungal prophylaxis and therapy of invasive candidiasis It hasan excellent pharmacokinetic and safety profile even in debilitatedpatients with good tissue penetration and a lack of major druginteractions particularly with immunosuppressive agents It can beprescribed in patients with renal failure if daily dosages are adaptedto the creatinine serum level Its spectrum of antimicrobial efficacyis reasonable and it remains active against most intrinsically sus-ceptible Candida spp encountered in systemic disease with lt5of C albicans resistant to fluconazole in that setting Although Ckrusei is intrinsically resistant to fluconazole it is rarely reported asa cause of systemic infection outside neutropenic patients Thus Cglabrata is the only species which might now limit the use offluconazole for the first line therapy of yeast fungaemia whenthe species is not identified Similarly patients who recentlyreceived fluconazole as antifungal prophylaxis should not be trea-ted with fluconazole for the curative treatment of a presumed orproven episode of systemic candidiasis The fungistatic effect offluconazole against Candida spp does not appear to influence theoutcome of candidaemic episodes at least in comparison withamphotericin B which is apparently fungicidal against Candidaspp Finally when summarizing its valuable properties the strongdemonstration of its efficacy in large randomized controlled trialsand selected clinical series its availability in various commercialpresentations and its current low cost fluconazole still remains aleading antifungal drug against susceptible Candida species

Transparency declarations

C C E H A L P R and F D have no conflicts to declareD W D In the past 5 years D W D has received grant supportfrom Astellas Merck Pfizer F2G OrthoBiotech Indevus Basileathe Fungal Research Trust the Wellcome Trust the National Insti-tute of Allergy and Infectious Diseases and the European Union Hehas been an advisorconsultant to Merck Basilea Vicuron (nowPfizer) Schering Plough Indevus F2G Nektar Daiichi SigmaTau Astellas PPL Therapeutics and Uriach He has been paid fortalks on behalf of Astellas Merck and Pfizer He holds foundershares in F2G Ltd and GBE Diagnostics Ltd and talks on behalf ofAstellas Merck and Gilead Sciences O L Speakers bureau forPfizer

References

1 Richardson K The discovery and profile of fluconazole J Chemo-

ther 1990 2 51ndash4

2 Richardson K Brammer KW Marriott MS et al Activity of

UK-49858 a bis-triazole derivative against experimental infections

with Candida albicans and Trichophyton mentagrophytes Antimicrob

Agents Chemother 1985 27 832ndash5

3 Vanrsquot Wout JW Mattie H van Furth R A prospective study of the

efficacyof fluconazole (UK-49858)againstdeep-seated fungal infections

J Antimicrob Chemother 1988 21 665ndash72Table

15

No

n-c

om

par

ativ

est

ud

ies

on

flu

con

azo

leas

cura

tiv

etr

eatm

ent

of

neo

nat

alca

nd

idae

mia

Ref

eren

ce

Nu

mb

ero

f

pat

ien

tsR

egim

enM

icro

bio

log

ical

cure

Sid

eef

fect

s

Dri

esse

net

al

22

02

1v

ery

low

bir

thw

eig

ht

5m

gk

gfo

r

1ndash

42

day

sm

ean

16

90

3

0

cyto

lyti

ch

epat

itis

Fas

anoet

al

21

54

05

mg

kg

for

2ndash

80

day

sm

ean

26

97

5

cy

toly

tic

hep

atit

is

Wai

ner

etal

21

61

91

0m

gk

go

nd

ay1

then

5m

gk

g

63

su

rviv

ing

32

fun

gal

free

dea

ths

NS

Hu

anget

al

21

71

8v

ery

low

bir

thw

eig

ht

3ndash

10

mg

kg

for

15

ndash1

73

day

sm

ean

34

6fi

rst

lin

etr

eatm

ent

83

13

afte

rA

MB

fail

ure

6

2

29

cy

toly

tic

hep

atit

is

Hu

tto

vaet

al

21

84

0v

ery

low

bir

thw

eig

ht

6m

gk

gfo

r6

ndash4

8d

ays

65

cu

rew

ith

ou

tre

lap

se5

cy

toly

tic

hep

atit

is

5

-ele

vat

edse

rum

crea

tin

ine

Gu

rpin

aret

al

21

92

42

ndash1

6m

gk

gfo

r

5ndash

72

day

sm

ean

25

96

8

an

aem

iao

rcy

toly

tic

hep

atit

is

Sch

war

zeet

al

11

53

5ndash

6m

gk

gfo

r3

wee

ks

mea

n2

17

8

4

cyto

lyti

ch

epat

itis

AM

B

amphote

rici

nB

ver

ylo

wbir

thw

eight

lt1500

g

NS

st

atis

tica

lly

not

signif

ican

t

Review

404

4 Vanrsquot Wout JW deGraeff-Meeder ER Paul LC et al Treatment of

two cases of cryptococcal meningitis with fluconazole Scand J Infect Dis

1988 20 193ndash8

5 Tucker RM Williams PL Arathoon EG et al Pharmacokinetics of

fluconazole in cerebrospinal fluid and serum in human coccidioidal

meningitis Antimicrob Agents Chemother 1988 32 369ndash73

6 ByrneWRWajszczukCPCryptococcalmeningitis in theacquired

immunodeficiency syndrome (AIDS) successful treatment with flucona-

zole after failure of amphotericin B Ann Intern Med 1988 108 384ndash5

7 HughesCE BeggsWH Action of fluconazole (UK-49858) in rela-

tion to other systemic antifungal azoles J Antimicrob Chemother 1987

19 171ndash4

8 DebruyneDClinicalpharmacokineticsof fluconazole insuperficial

and systemic mycoses Clin Pharmacokinet 1997 33 52ndash77

9 Brammer KW Coates PE Pharmacokinetics of fluconazole in

pediatric patients Eur J Clin Microbiol Infect Dis 1994 13 325ndash9

10 Schwarze R Penk A Pittrow L Administration of fluconazole in

children below 1 year of age Mycoses 1999 42 3ndash16

11 Schwarze R Penk A Pittrow L Treatment of candidal infections

with fluconazole in neonates and infants Eur J Med Res 2000 5 203ndash8

12 Thaler FBernardBTodMet al Fluconazolepenetration in cereb-

ral parenchyma in humans at steady stateAntimicrob Agents Chemother

1995 5 1154ndash6

13 Bozzette SA Gordon RL Yen A et al Biliary concentrations of

fluconazole in a patient with candidal cholecystitis case reportClin Infect

Dis 1992 4 701ndash3

14 Debruyne D Ryckelynck JP Moulin M et al Pharmacokinetics of

fluconazole in patients undergoing continuous ambulatory peritoneal dial-

ysis Clin Pharmacokinet 1990 18 491ndash8

15 Tod M Lortholary O Padoin C et al Intravenous penetration of

fluconazole during endophthalmitis Clin Microbiol Infect 1997 3 143ndash4

16 Urbak SF Degn T Fluconazole in the management of fungal ocu-

lar infections Ophthalmologica 1994 3 147ndash56

17 Fasano C OrsquoKeefe J Gibbs D Fluconazole treatment of children

with severe fungal infections not treatable with conventional agentsEur J

Clin Microbiol Infect Dis 1994 13 344ndash7

18 Aleck KA Bartley DL Multiple malformation syndrome following

fluconazole use in pregnancy report of an additional patient Am J Med

Genet 1997 72 253ndash6

19 Buijk SL Gyssens IC Mouton JW et al Pharmacokinetics of

sequential intravenous and enteral fluconazole in critically ill surgical

patients with invasive mycoses and compromised gastro-intestinal func-

tion Intensive Care Med 2001 27 115ndash21

20 El-Yazigi AEllisMErnstPet al Pharmacokinetics of oral flucona-

zole when used for prophylaxis in bone marrow transplant recipients

Antimicrob Agents Chemother 1997 41 914ndash17

21 Finch CK Green CA Self TH Fluconazole-carbamazepine inter-

action South Med J 2002 95 1099ndash100

22 Tucker RM Denning DW Hanson RH et al Interaction of azoles

with rifampin phenytoin and carbamazepine in vitro and clinical obser-

vations Clin Infect Dis 1992 14 165ndash74

23 Stockley IH Stockleyrsquos Drug Interactions A Source Book of Inter-

actions Their Mechanisms Clinical Importance and Management 6th

edn London UK Pharmaceutical Press 2002

24 von Moltke LL Greenblatt DJ Duan SX et al Inhibition of terfena-

dine metabolism in vitro by azole antifungal agents and by selective sero-

tonin reuptake inhibitor antidepressants relation to pharmacokinetic

interactions in vivo J Clin Psychopharmacol 1996 16 104ndash12

25 BrockmeyerNH Tillmann I Mertins L et al Pharmacokinetic inter-

action of fluconazole and zidovudine in HIV-positive patients Eur J Med

Res 1997 2 377ndash83

26 van Burik JA LeisenringW Myerson D et al The effect of prophy-

lactic fluconazole on the clinical spectrum of fungal diseases in bone

marrow transplant recipients with special attention to hepatic candidiasis

An autopsy study of 355 patients Medicine 1998 77 246ndash54

27 Wingard JR Antifungal chemoprophylaxis after blood andmarrow

transplantation Clin Infect Dis 2002 34 1386ndash90

28 GarbinoJLewDPRomandJAetalPreventionofsevereCandida

infections in nonneutropenic high-risk critically ill patients a randomized

double-blind placebo-controlled trial in patients treatedbyselectivediges-

tive decontamination Intensive Care Med 2002 28 1708ndash17

29 Gearhart MO Worsening of liver function with fluconazole and

review of azole antifungal hepatotoxicity Ann Pharmacother 1994 281177ndash81

30 Crerar-Gilbert A Boots R Fraenkel D et al Survival following ful-

minant hepatic failure from fluconazole induced hepatitis Anaesth Inten-

sive Care 1999 27 650ndash2

31 PappasPGKauffmanCAPerfect Jetal Alopeciaassociatedwith

fluconazole therapy Ann Intern Med 1995 123 354ndash7

32 Stevens DA Diaz M Negroni R et al Safety evaluation of chronic

fluconazole therapy Fluconazole Pan-American Study Group

Chemotherapy 1997 5 371ndash7

33 Anaissie EJ Kontoyiannis DP Huls C et al Safety plasma con-

centrations and efficacy of high-dose fluconazole in invasive mold infec-

tions J Infect Dis 1995 172 599ndash602

34 Gussenhoven MJ Haak A Peereboom-Wynia JD et al Stevens-

Johnson syndrome after fluconazole Lancet 1991 338 120

35 NovelliVHolzelHSafetyand tolerabilityof fluconazole inchildrenAntimicrob Agents Chemother 1999 43 1955ndash60

36 Koks CH Crommentuyn KM Hoetelmans RM et al Can

fluconazole concentrations in saliva be used for therapeutic drug mon-

itoring Ther Drug Monit 2001 4 449ndash53

37 Louie A Drusano GL Banerjee P et al Pharmacodynamics of

fluconazole in amurinemodel of systemic candidiasisAntimicrob Agents

Chemother 1998 42 1105ndash9

38 PittrowLPenkAPlasmaand tissueconcentrationsof fluconazole

and their correlation to breakpoints Mycoses 1997 40 25ndash32

39 Rex JH Pfaller MA Galgiani JN et al Development of interpretive

breakpoints forantifungalsusceptibility testing conceptual frameworkand

analysis of in vitro-in vivo correlation data for fluconazole itraconazole

and Candida infections Subcommittee on Antifungal Susceptibility Test-

ingof theNationalCommittee forClinical LaboratoryStandardsClin Infect

Dis 1997 24 235ndash47

40 Pfaller MA Diekema DJ Twelve years of fluconazole in clinical

practiceglobal trends inspeciesdistributionand fluconazolesusceptibility

of bloodstream isolatesofCandida International FungalSurveillancePar-

ticipant Group Clin Microbiol Infect 2004 10 Suppl 1 11ndash23

41 Tortorano AM Rigoni AL Biraghi E et al The European Confed-

eration of Medical Mycology (ECMM) survey of candidaemia in Italy anti-

fungal susceptibility patterns of 261 non-albicans Candida isolates from

blood J Antimicrob Chemother 2003 52 679ndash82

42 Pfaller MAMesser SA Boyken L et al Geographic variation in the

susceptibilities of invasive isolates of Candida glabrata to seven systemi-

cally active antifungal agents a global assessment from the ARTEMIS

Antifungal Surveillance Program conducted in 2001 and 2002 J Clin

Microbiol 2004 42 3142ndash6

43 Paya CV Fungal infections in solid-organ transplantation Clin

Infect Dis 1993 16 677ndash88

44 Singh N Wagener MM Marino IR et al Trends in invasive fungal

infections in liver transplant recipients correlation with evolution in trans-

plantation practices Transplantation 2002 73 63ndash7

45 Fung JJ Fungal infection in liver transplantation Transplant InfectDis 2002 4 18ndash23

46 Winston DJ Pakrasi A Busuttil RW Prophylactic fluconazole in

liver transplant recipientsA randomized double-blind placebo-controlled

trial Ann Intern Med 1999 131 729ndash37

47 Gladdy RA Richardson SE Davies HD et al Candida infection in

pediatric liver transplant recipients Liver Transpl Surg 1999 5 16ndash24

Review

405

48 Castaldo P Stratta RJ Wood RP et al Clinical spectrum of fungal

infections after orthotopic liver transplantation Arch Surg 1991 126149ndash56

49 Husain S Tollemar J Dominguez EA et al Changes in the spec-

trum and risk factors for invasive candidiasis in liver transplant recipients

prospective multicenter case-controlled study Transplantation 2003

75 2023ndash9

50 GeorgeMJ Snydman DRWerner BG et al The independent role

of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic

liver transplant recipients Boston Center for Liver Transplantation

CMVIG-Study Group Cytogam MedImmune Inc Gaithersburg Mary-

land Am J Med 1997 103 106ndash13

51 Dockrell DH Mendez JC Jones M et al Human herpesvirus 6

seronegativity before transplantation predicts the occurrence of fungal

infection in liver transplant recipientsTransplantation 1999 67 399ndash403

52 Tollemar J Ericzon BG Barkholt L et al Risk factors for deep

Candida infections in liver transplant recipients Transplant Proc 1990

22 1826ndash7

53 Lumbreras C Cuervas-Mons V Jara P et al Randomized trial of

fluconazole versus nystatin for the prophylaxis of Candida infection

following liver transplantation J Infect Dis 1996 174 583ndash8

54 Winston DJ Busuttil RW Randomized controlled trial of oral itra-

conazole solution versus intravenousoral fluconazole for prevention of

fungal infections in liver transplant recipients Transplantation 2002

74 688ndash95

55 Tortorano AM Viviani MA PaganoA et al Candida colonization in

orthotopic liver tranplantation fuconazole versus oral amphoericin B

J Mycol Med 1995 5 21ndash4

56 Kung N Fisher N Gunson B et al Fluconazole prophylaxis for

high-risk liver transplant recipients Lancet 1995 345 1234ndash5

57 Pappas PG Rex JH Sobel JD et al Guidelines for treatment of

candidiasis Clin Infect Dis 2004 38 161ndash89

58 PayaCV Prevention of fungal infection in transplantation TransplInfect Dis 2002 4 S46ndash51

59 LortholaryO Dupont B Antifungal prophylaxis during neutropenia

and immunodeficiency Clin Microbiol Rev 1997 10 477ndash504

60 Benedetti E Gruessner AC Troppmann C et al Intra-abdominal

fungal infections after pancreatic transplantation incidence treatment

and outcome J Am Coll Surg 1996 183 307ndash16

61 LumbrerasC Fernandez I Velosa J et al Infectious complications

following pancreatic transplantation incidence microbiological and clini-

cal characteristics and outcome Clin Infect Dis 1995 20 514ndash20

62 Patterson JE Epidemiology of fungal infections in solid organ

transplant patients Transpl Infect Dis 1999 1 229ndash36

63 Kusne S Furukawa H Abu-Elmagd K et al Infectious complica-

tions after small bowel transplantation in adults an update Transplant

Proc 1996 28 2761ndash2

64 Paterson DL Ndirangu M Kwak EJ et al Opportunistic infections

in solid-organ transplant recipients pre-treated with alumetuzumab In

Abstracts of the Forty-Fourth Interscience Conference on Antimicrobial

Agents and Chemotherapy Washington DC 2004 Abstract K-1427 p

357 American Society for Microbiology Washington DC USA

65 Kramer MR Marshall SE Starnes VA et al Infectious complica-

tions in heart-lung transplantation Analysis of 200 episodes Arch Intern

Med 1993 153 2010ndash6

66 Goodrich JMReedECMori M et al Clinical features and analysis

of risk factors for invasive candidal infection after marrow transplantation

J Infect Dis 1991 164 731ndash40

67 Dykewicz CA Centers for Disease Control and Prevention (US)

Infectious Diseases Society of America American Society of Blood and

MarrowTransplantation Summary of the guidelines for preventing oppor-

tunistic infections among hematopoietic stem cell transplant recipients

Clin Infect Dis 2001 33 139ndash44

68 Sable CA Donowitz GR Infections in bone marrow transplant

recipients Clin Infect Dis 1994 18 273ndash81

69 Goodman JLWinston DJ Greenfield RA et al A controlled trial of

fluconazole to prevent fungal infections in patients undergoing bone mar-

row transplantation N Engl J Med 1992 326 845ndash51

70 Slavin MA Osborne B Adams R et al Efficacy and safety of flu-

conazole prophylaxis for fungal infectionsaftermarrow transplantationmdasha

prospective randomized double-blind study J Infect Dis 1995 1711545ndash52

71 Marr KA Seidel K SlavinMA et al Prolonged fluconazole prophy-

laxis is associated with persistent protection against candidiasis-related

death in allogeneic marrow transplant recipients long-term follow-up of a

randomized placebo-controlled trial Blood 2000 96 2055ndash61

72 AlangadenGChandrasekar PH BaileyE et al Antifungal prophy-

laxis with low-dose fluconazole during bone marrow transplantation The

Bone Marrow Transplantation Team Bone Marrow Transplant 1994 14919ndash24

73 Wolff SN Fay J Stevens D et al Fluconazole versus low-dose

amphotericin B for the prevention of fungal infections in patients under-

going bonemarrow transplantation a study of theNorthAmericanMarrow

Transplant Group Bone Marrow Transplant 2000 25 853ndash9

74 Annaloro C Oriana A Tagliaferri E et al Efficacy of different pro-

phylactic antifungal regimens in bone marrow transplantation Haemato-

logica 1995 80 512ndash17

75 Winston DJ Maziarz RT Chandrasekar PH et al Intravenous and

oral itraconazole versus intravenous and oral fluconazole for long-term

antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant

recipients A multicenter randomized trial Ann Intern Med 2003 138705ndash13

76 MarrKACrippaF LeisenringWet al Itraconazoleversus flucona-

zole forpreventionof fungal infections inpatients receivingallogeneicstem

cell transplants Blood 2004 103 1527ndash33

77 MacMillan ML Goodman JL DeFor TE et al Fluconazole to pre-

vent yeast infections in bone marrow transplantation patients a random-

ized trial of high versus reduced dose and determination of the value of

maintenance therapy Am J Med 2002 112 369ndash79

78 Marr KA Seidel K White TC et al Candidemia in allogeneic blood

and marrow transplant recipients evolution of risk factors after the adop-

tion of prophylactic fluconazole J Infect Dis 2000 181 309ndash16

79 van Burik JA Ratanatharathorn V Stepan DE et al Micafungin

versus fluconazole for prophylaxis against invasive fungal infections dur-

ing neutropenia in patients undergoing hematopoietic stem cell trans-

plantation Clin Infect Dis 2004 39 1407ndash16

80 Prentice HG Kibbler CC Prentice AG Towards a targeted risk-

based antifungal strategy in neutropenic patients Br J Haematol 2000

110 273ndash84

81 Laverdiere M Rotstein C Bow EJ et al Impact of fluconazole

prophylaxis on fungal colonizatin and infection rates in neutropenic

patients The Canadian Fluconazole Study J Animicrob Chemother

2000 46 1001ndash8

82 Winston DJ Chandrasekar PH Lazarus HM et al Fluconazole

prophylaxis of fungal infections in patients with acute leukemia Results

of a randomized placebo-controlled double-blind multicenter trial Ann

Intern Med 1993 118 495ndash503

83 Chandrasekar PHGatnyCMEffect of fluconazole prophylaxis on

fever and use of amphotericin in neutropenic cancer patients Bone Mar-

row Transplantation Team Chemotherapy 1994 40 136ndash43

84 Rotstein C Bow EJ Laverdiere M et al Randomized placebo-

controlled trial of fluconazole prophylaxis for neutropenic cancer patients

benefit basedonpurposeand intensity of cytotoxic therapy TheCanadian

Fluconazole Prophylaxis Study Group Clin Infect Dis 1999 28 331ndash40

85 YamacK Senol E HaznedarR Prophylactic use of fluconazole in

neutropenic cancer patients Postgrad Med J 1997 71 284ndash6

86 KernW BehreG Rudolf T et al Failure of fluconazole prophylaxis

to reducemortality or the requirement of systemic amphotericin B therapy

during treatment for refractory acute myeloid leukemia results of a

Review

406

prospective randomized phase III study German AML Cooperative

Group Cancer 1998 83 291ndash301

87 SchaffnerA SchaffnerM Effect of prophylactic fluconazole on the

frequencyof fungal infectionsamphotericinBuseandhealthcarecosts in

patients undergoing intensive chemotherapy for hematologic neoplasias

J Infect Dis 1995 172 1035ndash41

88 Egger T Gratwohl A Tichelli A et al Comparison of fluconazole

with oral polyenes in the prevention of fungal infections in neutropenic

patients A prospective randomized single-center study Support Care

Cancer 1995 3 139ndash46

89 Morgenstern GR Prentice AG Prentice H et al A randomized

controlled trial of itraconazole versus fluconazole for the prevention of

fungal infections in patients with haematological malignancies UK Mul-

ticentre Antifungal Prophylaxis Study Group Br J Haematol 1999 105901ndash11

90 EllisMEClinkHErnstPetalControlledstudyof fluconazole in the

preventionof fungal infections in neutropenic patientswith haematological

malignancies and bone marrow transplant recipients Eur J Clin Microbiol

Infect Dis 1994 13 3ndash11

91 Philpott-Howard JN Wade JJ Mufti GJ et al Randomized com-

parisonoforal fluconazoleversusoralpolyenes for thepreventionof fungal

infection in patients at risk of neutropenia Multicentre Study Group

J Antimicrob Chemother 1993 31 973ndash84

92 Ninane J A multicentre study of fluconazole versus oral polyenes

in the prevention of fungal infection in children with hematological or

oncological malignancies Multicentre Study Group Eur J Clin Microbiol

Infect Dis 1994 13 330ndash7

93 Menichetti F Del Favero A Martino P et al Preventing fungal

infection in neutropenic patients with acute leukemia fluconazole com-

pared with oral amphotericin B The GIMEMA Infection Program Ann

Intern Med 1994 120 913ndash18

94 Akiyama H Mori S Tanikawa S et al Fluconazole versus oral

amphotericin B in preventing fungal infection in chemotherapy-induced

neutropenic patients with haematological malignancies Mycoses 1996

36 373ndash8

95 Meunier F AounM JanssensM et al Chemoprophylaxis of fungal

infections in granulocytopenic patients using fluconazole versus oral

amphotericin B Drug Invest 1991 3 258ndash65

96 Rozenberg-Arska M Dekker AW Branger J et al A randomized

study to compare oral fluconazole to amphotericin B in the prevention of

fungal infections inpatientswithacute leukaemiaJAntimicrobChemother

1991 27 369ndash76

97 Brammer KW Management of fungal infection in neutropenic

patients with fluconazole Haematol Blood Transfus 1990 33 546ndash50

98 Bodey GP Anaissie EJ Elting LS et al Antifungal prophylaxis

during remission induction therapy for acute leukemia fluconazole versus

intravenous amphotericin B Cancer 1994 73 2099ndash106

99 Kanda Y Yamamoto R Chizuka A et al Prophylactic action of

oral fluconazole against fungal infection in neutropenic patients A

meta-analysis of 16 randomized controlled trials Cancer 2000 891611ndash25

100 Bow EJ Laverdiere M Lussier N et al Antifungal prophylaxis for

severely neutropenic chemotherapy recipients a meta analysis of

randomized-controlled clinical trials Cancer 2002 94 3230ndash46

101 Viscoli C Paesmans M Sanz M et al Association between

antifungal prophylaxis and rate of documented bacteremia in febrile

neutropenic cancer patients Clin Infect Dis 2001 32 1532ndash7

102 HughesWT Armstrong D BodeyGP et al 2002 guidelines for the

use of antimicrobial agents in neutropenic patients with cancerClin Infect

Dis 2002 34 730ndash51

103 Cornely OA Bohme A Buchheidt D et al Prophylaxis of invasive

fungal infections in patients with hematological malignancies and solid

tumorsmdashguidelines of the Infectious Diseases Working Party (AGIHO)

of the German Society of Hematology and Oncology (DGHO) Ann

Hematol 2003 82 Suppl 2 186ndash200

104 McNeil MM Nash SL Hajjeh RA et al Trends in mortality due to

invasivemycotic diseases in theUnitedStates 1980ndash1997Clin InfectDis

2001 33 641ndash7

105 KibblerCCSeatonSBarnesRA et alManagement and outcome

of bloodstream infections due to Candida species in England and Wales

J Hosp Infect 2003 54 18ndash24

106 Marchetti O Bille J Fluckiger U et al Fungal Infection Network of

Switzerland Epidemiology of candidemia in Swiss tertiary care hospitals

secular trends 1991-2000 Clin Infect Dis 2004 38 311ndash20

107 Gudlaugsson O Gillespie S Lee K et al Attributable mortality of

nosocomial candidemia revisited Clin Infect Dis 2003 37 1172ndash7

108 Ibanez-Nolla J Nolla-Salas M Leon MA et al Early diagnosis of

candidiasis in nonneutropenic critically ill patients J Infect 2004 48181ndash92

109 BlumbergHMJarvisWRSoucieJMetalRisk factors for candidal

bloodstream infections in surgical intensive care unit patients the NEMIS

prospective multicenter study The National Epidemiology of Mycosis

Survey Clin Infect Dis 2001 33 177ndash86

110 Pittet D Monod M Suter PM et al Candida colonization and

subsequent infections in critically ill surgical patients Ann Surg 1994

220 751ndash8

111 Sendid B Poirot JL Tabouret M et al Combined detection of

mannanaemia and antimannan antibodies as a strategy for the diagnosis

of systemic infectioncausedbypathogenicCandidaspeciesJMedMicro-

biol 2002 51 433ndash42

112 Bar W Hecker H Diagnosis of systemic Candida infections in

patients of the intensive care unit Significance of serum antigens and

antibodies Mycoses 2002 45 22ndash8

113 Calandra T Marchetti O Clinical trials of antifungal prophy-

laxis among patients undergoing surgery Clin Infect Dis 2004 39S185ndash92

114 Sypula WT Kale-Pradhan PB Therapeutic dilemma of flucona-

zole prophylaxis in intensive care Ann Pharmacother 2002 36 155ndash9

115 Pelz RK Hendrix CW Swoboda SM et al Double-blind placebo-

controlled trial of fluconazole to prevent candidal infections in critically ill

surgical patients Ann Surg 2001 233 542ndash8

116 Eggimann P Francioli P Bille J et al Fluconazole prophylaxis

prevents intraabdominal candidiasis in high-risk surgical patients Crit

Care Med 1997 27 1066ndash72

117 Swoboda SM Merz WG Lipsetta PA Candidemia the impact of

antifungal prophylaxis in a surgical intensive care unitSurg Infect20034345ndash54

118 Todd JC OrsquoNeal VG Grady KP et al Reduction of secondary

mycotic infections in the trauma intensivie care unit with fluconazole

J Trauma 1991 31 1722ndash27

119 Jacobs S Price Evans DA Tariq M et al Fluconazole improves

survival in septic shock a randomized double-blind prospective studyCrit

Care Med 2003 31 1938ndash46

120 Zervos EE Fink GW Norman JG et al Fluconazole increases

bactericidal activity of neutrophils through non-cytokine-mediated path-

way J Trauma 1996 41 465ndash70

121 AblesAZBlumerNAValainisGTetal Fluconazoleprophylaxis of

severe Candida infection in trauma and postsurgical patients a prospec-

tive double-blind randomised placebo-controlled trial Infect Dis Clin

Pract 2000 9 169ndash75

122 Kam LW Lin JD Management of systemic candidal infections in

the intensive care unit Am J Health Syst Pharm 2002 59 33ndash41

123 Rocco TR Reinert SE Simms HH Effects of fluconazole admin-

istration in critically ill patients analysis of bacterial and fungal resistance

Arch Surg 2000 135 160ndash5

124 Tortorano AM Caspani L Rigoni AL et al Candidosis in the inten-

sive care unit a 20-year survey J Hosp Infect 2004 57 8ndash13

125 EggimannPGarbino J Pittet DManagement ofCandida species

infections in critically ill patients Lancet Infect Dis 2003 3 772ndash85

Review

407

126 EggimannPGarbinoJPittetDEpidemiologyofCandida species

infections incritically ill non-immunosuppressedpatientsLancet InfectDis

2003 3 685ndash702

127 Martins MD Lozano-Chiu M Rex JH Declining rates of oropha-

ryngeal candidiasis and carriage of Candida albicans associated with

trends toward reduced rates of carriage of fluconazole-resistant C albi-

cans in human immunodeficiency virus-infected patients Clin Infect Dis

1998 27 1291ndash4

128 Powderly WG Finkelstein D Feinberg J et al A randomized trial

comparing fluconazole with clotrimazole troches for the prevention of fun-

gal infections in patients with advanced human immunodeficiency virus

infection NIAID AIDS Clinical Trials Group N Engl J Med 1995 332700ndash5

129 Leen CL Dunbar EM Ellis ME et al Once-weekly fluconazole to

prevent recurrenceof oropharyngeal candidiasis inpatientswithAIDSand

AIDS-related complex a double-blind placebo-controlled study J Infect

1990 21 55ndash60

130 Stevens DA Greene SI Lang OS Thrush can be prevented in

patients with acquired immunodeficiency syndrome and the acquired

immunodeficiency syndrome-related complex Randomized double-

blind placebo-controlled study of 100-mg oral fluconazole daily Arch

Intern Med 1991 151 2458ndash64

131 Just-Nubling G Gentschew G Meissner K Fluconazole prophy-

laxis of recurrent oral candidiasis inHIV-positive patientsEur JClinMicro-

biol Infect Dis 1991 10 917ndash21

132 Marriott DJ Jones PD Hoy JF et al Fluconazole once a week as

secondary prophylaxis against oropharyngeal candidiasis in HIV-infected

patients A double-blind placebo-controlled studyMed J Aust 1993 158312ndash16

133 Schuman P Capps L Peng G et al Weekly fluconazole for the

prevention ofmucosal candidiasis inwomenwithHIV infection A random-

ized double-blind placebo-controlled trial Terry Beirn Community Pro-

grams for Clinical Research on AIDSAnn InternMed 1997 126 689ndash96

134 Havlir DV DubeMPMcCutchan JA et al Prophylaxis with weekly

versus daily fluconazole for fungal infections in patients with AIDS Clin

Infect Dis 1998 27 1369ndash75

135 Pagani JL Chave JP Casjka C et al Efficacy tolerability and

development of resistance in HIV-positive patients treated with flucona-

zole for secondary prevention of oropharyngeal candidiasis a random-

ized double-blind placebo-controlled trial JAntimicrobChemother 2002

50 231ndash40

136 Vazquez JA Peng G Sobel JD et al Evolution of antifungal sus-

ceptibility amongCandidaspecies isolates recovered fromhuman immun-

odeficiency virus-infected women receiving fluconazole prophylaxis Clin

Infect Dis 2001 33 1069ndash75

137 Delfraissy JF Prise en charge therapeutique des patients infectespas le VIH Rapport Delfraissy Paris Flammarion 2004

138 DePauwBERaemaekers JMDonnelly JPet al Anopenstudyon

the safety and efficacy of fluconazole in the treatment of disseminated

Candida infections in patients treated for hematological malignancy Ann

Hematol 1995 70 83ndash7

139 Anaissie EJ Vartivarian SE Abi-Said D et al Fluconazole versus

amphotericin B in the treatment of hematogenous candidiasis a matched

cohort study Am J Med 1996 101 170ndash6

140 Anaissie EJ Darouiche RO Abi-Said D et al Management of

invasive candidal infections results of a prospective randomized multi-

center study of fluconazole versus amphotericin B and review of the

literature Clin Infect Dis 1996 23 964ndash72

141 Myoken Y Kyo T Kohara T et al Breakthrough fungemia caused

by azole-resistant Candida albicans in neutropenic patients with acute

leukemia Clin Infect Dis 2003 36 1496ndash7

142 Anttila VJ FarkkilaM JanssonSE et al Diagnostic laparoscopy in

patientswith acute leukemiaandsuspectedhepatic candidiasisEur JClin

Microbiol Infect Dis 1997 16 637ndash43

143 Anaissie E Bodey GP Kantarjian H et al Fluconazole therapy for

chronic disseminated candidiasis in patients with leukemia and prior

amphotericin B therapy Am J Med 1991 91 142ndash50

144 KauffmanCA BradleySFRossSC et al Hepatosplenic candidia-

sis successful treatment with fluconazole Am J Med 1991 91 137ndash41

145 Kontoyiannis DP Luna MA Samuels BI et al Hepatosplenic can-

didiasis A manifestation of chronic disseminated candidiasis Infect Dis

Clin North Am 2000 14 721ndash39

146 Graninger W Presteril E Schneeweiss B et al Treatment of

Candida albicans fungaemia with fluconazole J Infect 1993 26 133ndash46

147 Phillips P Shafran S Garber G et al Multicenter randomized trial

of fluconazole versus amphotericin B for treatment of candidemia in

non-neutropenic patients Canadian Candidemia Study Group Eur J

Clin Microbiol Infect Dis 1997 16 337ndash45

148 Rex JH Bennett JE Sugar AM et alA randomized trial comparing

fluconazolewithamphotericinB for the treatmentof candidemia inpatients

without neutropenia Candidemia Study Group and the National Institute

N Engl J Med 1994 331 1325ndash30

149 Abele-Horn M Kopp A Sternberg U et al A randomized study

comparing fluconazolewith amphotericinB5-flucytosine for the treatment

of systemic Candida infections in intensive care patients Infection 1996

24 426ndash32

150 Nguyen MH Peacock JE Jr Tanner DC et al Therapeutic

approaches in patients with candidemia Evaluation in a multicenter

prospective observational study Arch Intern Med 1995 155 2429ndash35

151 Rex JH Pappas PG Karchmer AW et al A randomized and

blinded multicenter trial of high-dose fluconazole plus placebo versus flu-

conazole plus amphotericin B as therapy for candidemia and its con-

sequences in non-neutropenic subjectsClin Infect Dis 2003 36 1221ndash8

152 Mora-Duarte J Betts R Rotstein C et al Comparison of

caspofungin and amphotericin B for invasive candidiasis N Engl J Med

2002 347 2020ndash9

153 Sugar AM Saunders C Diamond RD et al Successful treatment

of Candida osteomyelitis with fluconazole A noncomparative study of

two patients Diagn Microbiol Infect Dis 1990 13 517ndash20

154 Tang C Successful treatment of Candida albicans osteomyelitis

with fluconazole J Infect 1993 26 89ndash92

155 LafontAOliveAGelmanMet alCandidaalbicansspondylodisci-

tis and vertebral osteomyelitis in patients with intravenous heroin drug

addiction Report of 3 new cases J Rheumatol 1994 21 953ndash6

156 Hennequin C Bouree P Hiesse C et al Spondylodiskitis due to

Candida albicans report of two patients who were successfully treated

with fluconazole and review of the literature Clin Infect Dis 1996 23176ndash8

157 Jonnalagadda S VeerabaguMP Rakela J et alCandida albicans

osteomyelitis in a liver transplant recipient a case report and review of the

literature Transplantation 1996 62 1182ndash4

158 Rossel P Schonheyder HC Nielsen H Fluconazole therapy

inCandidaalbicansspondylodiscitisScandJ InfectDis199830 527ndash30

159 TurnerDLJohnsonSARuleSASuccessful treatmentof candidal

osteomyelitis with fluconazole following failure with liposomal ampho-

tericin B J Infect 1999 38 51ndash3

160 El-Zaatari MM Hulten K Fares Y et al Successful treatment of

Candida albicans osteomyelitis of the spine with fluconazole and surgical

debridement case report J Chemother 2002 14 627ndash30

161 Seravalli L Van Linthoudt D Bernet C et al Candida glabrata

spinal osteomyelitis involving two contiguous lumbar vertebrae a case

report and review of the literature Diagn Microbiol Infect Dis 2003 45137ndash41

162 Garbino J Schnyder I LewDP et al An unusual cause of vertebral

osteomyelitis Candida species Scand J Infect Dis 2003 35 288ndash91

163 TunkelARThomasCYWispelweyBCandidaprostheticarthritis

report of a case treated with fluconazole and review of the literature Am J

Med 1993 94 100ndash3

Review

408

164 CushingRD FulgenziWR Synovial fluid levels of fluconazole in a

patient with Candida parapsilosis prosthetic joint infection who had an

excellent clinical response J Arthroplasty 1997 12 950

165 Fukasawa N Shirakura K Candida arthritis after total knee

arthroplastymdasha case of successful treatment without prosthesis removal

Acta Orthop Scand 1997 68 306ndash7

166 Lerch K Kalteis T Schubert T et al Prosthetic joint infections with

osteomyelitis due to Candida albicans Mycoses 2003 46 462ndash6

167 Clancy CJ Nguyen MH Morris AJ Candidal mediastinitis an

emerging clinical entity Clin Infect Dis 1997 25 608ndash13

168 PetrikkosGSkiadaA SabatakouH et al Case report Successful

treatment of two cases of post-surgical sternal osteomyelitis due to

Candida krusei and Candida albicans respectively with high doses of

triazoles (fluconazole itraconazole) Mycoses 2001 44 422ndash5

169 Weers-Pothoff GHavermans JF Kamphuis J et alCandida tropi-

calis arthritis in a patient with acutemyeloid leukemia successfully treated

with fluconazole case report and review of the literature Infection 1997

25 109ndash11

170 Laatikainen L TuominenM vonDickhoff K Treatment of endoge-

nous fungal endophthalmitis with systemic fluconazole with or without

vitrectomy Am J Ophthalmol 1992 113 205ndash7

171 Borne MJ Elliott JH OrsquoDay DM Ocular fluconazole treatment of

Candidaparapsilosisendophthalmitis after failed intravitreal amphotericin

B Arch Ophthalmol 1993 111 1326ndash7

172 Zarbin MA Becker E Witcher J et al Treatment of presumed

fungal endophthalmitis with oral fluconazole Ophthalmic Surg Lasers

1996 27 628ndash31

173 WongVK TasmanWEagleRC et al BilateralCandida parapsilo-

sis endophthalmitis Arch Ophthalmol 1997 115 670ndash2

174 Kauffman CA Bradley SF Vine AK Candida endophthalmitis

associated with intraocular lens implantation efficacy of fluconazole ther-

apy Mycoses 1993 36 13ndash17

175 del Palacio A Cuetara MS Ferro M et al Fluconazole in the man-

agement of endophthalmitis in disseminated candidosis of heroin addicts

Mycoses 1993 36 193ndash9

176 Luttrull JK Wan WL Kubak BM et al Treatment of ocular fungal

infections with oral fluconazole Am J Ophthalmol 1995 119 477ndash81

177 Akler ME Vellend H McNeely DM et al Use of fluconazole in the

treatment of candidal endophthalmitis Clin Infect Dis 1995 20 657ndash64

178 Christmas NJ Smiddy WE Vitrectomy and systemic fluconazole

for treatment of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1996 27 1012ndash18

179 EssmanTFFlynnHWSmiddyWEet al Treatment outcomes in a

10-year study of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1997 28 185ndash94

180 Martinez-Vazquez C Fernandez-Ulloa J Bordon J et al Candida

albicans endophthalmitis in brown heroin addicts response to early vit-

rectomyprecededand followedbyantifungal therapyClin InfectDis1998

27 1130ndash3

181 Aleixo MJ Caldeira L Ferreira ML Candida albicans meningitis

clinical case J Infect 2000 40 191ndash2

182 InoueY YozuR Ueda T et al A case report ofCandida parapsilo-

sis endocarditis J Heart Valve Dis 1998 7 240ndash2

183 Isalska BJ Stanbridge TN Fluconazole in the treatment of candi-

dal prosthetic valve endocarditis BMJ 1988 297 178ndash9

184 Martino P Meloni G Cassone A Candidal endocarditis and treat-

ment with fluconazole and granulocyte-macrophage colony-stimulating

factor Ann Intern Med 1990 112 966ndash7

185 Roupie E Darmon JY Brochard L et al Fluconazole therapy of

candidal native valveendocarditisEur JClinMicrobiol InfectDis199110458ndash9

186 Hernandez JA Gonzalez-Moreno M Llibre JM et al Candidal

mitral endocarditis and long-term treatment with fluconazole in a patient

with human immunodeficiency virus infection Clin Infect Dis 1992 151062ndash3

187 Venditti MDeBernardis FMicozzi A et al Fluconazole treatment

of catheter-related right-sided endocarditis caused by Candida albicans

and associated with endophthalmitis and folliculitis Clin Infect Dis 1992

14 422ndash6

188 Wallbridge DR McCartney AC Richardson MD Fluconazole in

the treatment ofCandidaprosthetic valveendocarditisMycoses199336259ndash61

189 Otaki M Kitamura N Candida prosthetic valve endocarditis An

autopsy review Int Surg 1993 78 252ndash3

190 Czwerwiec FS Bilsker MS Kamerman ML et al Long-term sur-

vival after fluconazole therapy of candidal prosthetic valve endocarditis

Am J Med 1993 94 545ndash6

191 Thakur RK Skelcy KM Kahn RN et al Successful treatment of

Candida prosthetic valve endocarditis with a combination of fluconazole

and amphotericin B Crit Care Med 1994 22 712ndash14

192 Cancelas JA Lopez JCabezudoE et al Native valve endocarditis

due toCandida parapsilosis a late complication after bonemarrow trans-

plantation-related fungemia Bone Marrow Transplant 1994 13 333ndash4

193 Zahid MA Klotz SA Hinthorn DR Medical treatment of recurrent

candidemia in a patient with probable Candida parapsilosis prosthetic

valve endocarditis Chest 1994 105 1597ndash8

194 Wells CJ Leech G Lever AM et al Treatment of native valve

Candida endocarditis with fluconazole J Infect 1995 31 233ndash5

195 Gilbert HM Peters ED Lang SJ et al Successful treatment of

fungal prosthetic valve endocarditis case report and review Clin Infect

Dis 1996 22 348ndash54

196 Nguyen MH Nguyen ML Yu VL et al Candida prosthetic valve

endocarditis prospective study of six cases and review of the literature

Clin Infect Dis 1996 22 262ndash7

197 Lejko-Zupanc T Kozelj M A case of recurrent Candida parapsilo-

sis prosthetic valve endocarditis cure bymedical treatment alone J Infect

1997 35 81ndash2

198 Joly V BelmatougN Leperre A et al Pacemaker endocarditis due

to Candida albicans case report and review Clin Infect Dis 1997 251359ndash62

199 Rex JH Walsh T Sobel JD et al Practice guidelines for the treat-

mentof candidiasis InfectiousDiseasesSocietyofAmericaClin InfectDis

2000 30 662ndash78

200 Baddour LM Long-term suppressive therapy for Candida para-

psilosis-induced prosthetic valve endocarditis Mayo Clin Proc 1995

70 773ndash5

201 Melgar GR Nasser RM Gordon SM Fungal prosthetic valve

endocarditis in 16 patients An 11-year experience in a tertiary care hos-

pital Medicine 1997 76 94ndash103

202 Dupont H Paugam-Burtz C Muller-Serieys C et al Predictive

factors of mortality due to polymicrobial peritonitis with Candida isolation

in peritoneal fluid in critically ill patients Arch Surg 2002 137 1341ndash6

203 Lee SC FungCP ChenHY et alCandida peritonitis due to peptic

ulcer perforation incidence rate risk factors prognosis and susceptibility

to fluconazole and amphotericin B Diagn Microbiol Infect Dis 2002 4423ndash7

204 Levine J Bernard DB Idelson BA et al Fungal peritonitis compli-

cating continuous ambulatory peritoneal dialysis successful treatment

with fluconazole a new orally active antifungal agent Am J Med 1989

86 825ndash7

205 Michel C Courdavault L al Khayat R et al Fungal peritonitis in

patients on peritoneal dialysis Am J Nephrol 1994 14 113ndash20

206 WangAYYuAWLi PKet al Factors predicting outcomeof fungal

peritonitis in peritoneal dialysis analysis of a 9-year experience of fungal

peritonitis in a single center Am J Kidney Dis 2000 36 1183ndash92

207 Hawkins JL Baddour LM Candida lusitaniae infections in the era

of fluconazole availability Clin Infect Dis 2003 36 14ndash18

Review

409

208 KauffmanCAVazquezJASobel JDetal Prospectivemulticenter

surveillance study of funguria in hospitalized patients The National Insti-

tute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group

Clin Infect Dis 2000 30 14ndash18

209 Sobel JD Kauffman CA McKinsey D et al Candiduria a random-

ized double-blind study of treatment with fluconazole and placebo The

National Institute of Allergy and Infectious Diseases (NIAID) Mycoses

Study Group Clin Infect Dis 2000 30 19ndash24

210 LundstromTSobel JNosocomial candiduria a reviewClin Infect

Dis 2001 32 1602ndash7

211 Kaufman D Boyle R Hazen KC et al Fluconazole prophylaxis

against fungal colonization and infection in preterm infants N Engl J

Med 2001 345 1660ndash6

212 Kicklighter SD Springer SC Cox T et al Fluconazole for the pro-

phylaxis against candidal rectal colonization in the very low birth weight

infant Pediatrics 2001 107 293ndash8

213 McGuire W Clerihew L Austin N Prophylactic intravenous anti-

fungal agents to prevent mortality and morbidity in very low birth weight

infants Cochrane Database Syst Rev 2004 CD003850

214 Agarwal JBansalSMalikGKetal Trends inneonatal septicemia

emergence of non-albicans Candida Indian Pediatr 2004 41 712ndash15

215 FasanoCOrsquoKeefe JGibbsD Fluconazole treatment of neonates

and infants with severe fungal infections not treatable with conventional

agents Eur J Clin Microbiol Infect Dis 1994 13 351ndash4

216 Wainer S Cooper PA Gouws H et al Prospective study of flu-

conazole therapy in systemicneonatal fungal infectionPediatr InfectDis J

1997 16 763ndash7

217 Huang YC Lin TY Lien RI et al Fluconazole therapy in neonatal

candidemia Am J Perinatol 2000 17 411ndash15

218 Huttova M Hartmanova I Kralinsky K et al Candida fungemia in

neonates treated with fluconazole report of forty cases including eight

with meningitis Pediatr Infect Dis J 1998 17 1012ndash15

219 Gurpinar AN Balkan E Kilic N et al Fluconazole treatment of

neonates and infants with severe fungal infections J Int Med Res 1997

25 214ndash18

220 Driessen M Ellis JB Muwazi F et al The treatment of systemic

candidiasis in neonates with oral fluconazole Ann Trop Pediatr 1997 17263ndash71

221 Driessen M Ellis JB Cooper PA et al Fluconazole vs

amphotericin B for the treatment of neonatal fungal septicemia

a prospective randomized trial Pediatr Infect Dis J 1997 151107ndash12

222 Marr B Gross S Cunningham C et al Candidal sepsis and

meningitis in a very-low-birth-weight infant successfully treated with flu-

conazole and flucytosine Clin Infect Dis 1994 19 795ndash6

223 Oleinik EM Della-Latta P Rinaldi MG et al Candida lusitaniae

osteomyelitis in a premature infant Am J Perinatol 1993 10 313ndash15

224 Mondal RK Singhi SC Chakrabarti A Randomized comparison

between fluconazole and itraconazole for the treatment of candidemia in a

pediatric intensive care unit a preliminary study Pediatr Crit Care Med

2004 5 561ndash5

225 Viscoli C Castagnola E Fioredda F et al Fluconazole in the treat-

ment of candidiasis in immunocompromised children Antimicrob Agents

Chemother 1991 35 365ndash7

226 Decruyenaere J Colardyn F Vogelaers D et al Combined use of

fluconazole and selective digestive decontamination in the prevention of

fungal infection after adult liver transplantation Transplant Proc 1995 273515ndash16

227 Koh LP Kurup A Goh YT et al Randomized trial of fluconazole

versus low-dose amphotericin B in prophylaxis against fungal infections in

patients undergoing hematopoietic stem cell transplantationAmJHema-

tol 2002 71 260ndash7

228 Gluckman E Esperou-Bourdeau H Ribaud P et al Comparaison

entre le fluconazole et le ketoconazole pour la prophylaxie des infections

fongiques chez les patients traites par greffe de moelle allogenique Cah

Oncol 1993 2 167ndash9

Review

410

Table

14

Rep

ort

so

fp

atie

nts

wit

hen

do

card

itis

du

eto

Candida

sp

and

trea

ted

wit

hfl

uco

naz

ole

Ref

eren

ce

Val

vu

lar

inv

olv

emen

tCandida

spec

ies

Nu

mb

ero

f

pat

ien

ts

Dose

of

fluco

naz

ole

(mg

day

)

Tre

atm

ent

du

rati

on

Ass

oci

ated

trea

tmen

ts

Eff

icac

y(f

oll

ow

-up

du

rati

on

)

Ino

ueet

al

18

2ao

rtic

val

ve

Cparapsilosis

16

00

then

40

01

8m

on

ths

surg

ery

reco

ver

y(1

8m

on

ths)

Lej

ko

-Zu

pan

cet

al

19

7m

itra

lp

rost

hes

isCparapsilosis

14

00

(14

day

s)th

en1

00

8m

on

ths

AM

B(3

9g

)A

BC

D

(15

g)

no

rep

lace

men

t

reco

ver

y(gt

3y

ears

)

Joly

etal

19

8p

acem

aker

Calbicans

14

00

(6d

ays)

then

20

07

mo

nth

ssu

rger

yre

cov

ery

(18

mo

nth

s)

Ng

uy

enet

al

19

6ao

rtic

pro

sth

esis

Calbicans

14

00

then

20

04

5y

ears

AM

B+

5F

C

12

wee

ks

no

rep

lace

men

t

reco

ver

y(5

5y

ears

)

Gil

ber

tet

al

19

5ao

rtic

pro

sth

esis

Calbicans

12

00

8m

on

ths

surg

ery

AM

B(2

g)

+

5F

C

40

day

s

reco

ver

y(9

mo

nth

s)

Wel

lset

al

19

4m

itra

lan

dtr

icu

spid

val

ves

Calbicans

12

00

ndash4

00

(14

day

s)

then

40

0th

en5

0

65

mo

nth

s

(40

0m

g)

and

10

mo

nth

s

(50

mg

)

no

rep

lace

men

tre

cov

ery

(45

yea

rs)

Zah

idet

al

19

3m

itra

lv

alv

e

(pro

bab

le)

Cparapsilosis

14

00

18

mo

nth

sA

MB

(5g

)+

5F

C

ket

oco

naz

ole

(80

0m

gd

ay

4m

on

ths)

no

rep

lace

men

t

reco

ver

y(5

yea

rs)

Can

cela

set

al

19

2m

itra

lv

alv

eCparapsilosis

12

00

4m

on

ths

surg

ery

A

MB

(2g

)re

cov

ery

(4m

on

ths)

Th

aku

ret

al

19

1ao

rtic

pro

sth

esis

Calbicans

12

00

6w

eek

sA

MB

(30

mg

day

)

6w

eeks

no

repla

cem

ent

reco

ver

y(2

6m

on

ths)

Czw

erw

iecet

al

19

0ao

rtic

pro

sth

esis

Cparapsilosis

14

00

26

mo

nth

sA

MB

(72

5m

g)

no

rep

lace

men

t

reco

ver

y(2

6m

on

ths)

Ota

kiet

al

18

9m

itra

lp

rost

hes

isCparapsilosis

1u

nsp

ecif

ied

68

day

sn

ore

pla

cem

ent

fail

ure

(dea

thd

ue

toce

reb

ral

hae

mo

rrh

age

and

fev

er)

Wal

lbri

dg

eet

al

18

8m

itra

lp

rost

hes

isCparapsilosis

12

00

-40

0gt

7w

eek

sA

MB

(30

0m

g)

no

rep

lace

men

t

reco

ver

y(6

mo

nth

s)

Ven

dit

tiet

al

18

7in

tera

tria

lse

ptu

mCalbicans

12

00

(28

day

s)th

en6

00

(11

day

s)th

en4

00

6m

on

ths

no

rep

lace

men

tre

cov

ery

(14

mo

nth

s)

Her

nan

dez

etal

18

6m

itra

lv

alv

eCalbicans

12

00

3m

on

ths

AM

Bfa

ilu

ren

o

rep

lace

men

t

imp

rov

emen

t(3

mo

nth

s)

Ro

up

ieet

al

18

5ao

rtic

val

ve

Ctropicalis

14

00

50

day

sn

ore

pla

cem

ent

reco

ver

y(1

1m

on

ths)

Mar

tin

oet

al

18

4in

tera

tria

lse

ptu

mCparapsilosis

13

mg

kg

(7d

ays)

then

6m

gk

g

gt3

mo

nth

sG

M-C

SF

(gt6

wee

ks)

no

rep

lace

men

t

reco

ver

y(5

mo

nth

s)

Isal

skaet

al

18

3m

itra

lp

rost

hes

isCparapsilosis

11

00

ndash2

00

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ore

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ent

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r)

AM

B

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ote

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FC

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ne

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CD

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ph

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Review

402

favoured by indwelling urinary catheters immunosuppressivedrugs or antibiotic prescriptions diabetes mellitus and extremeages C albicans is involved in half of the cases followed byC glabrata in 15 of the cases In 10 of cases infection involvesmore than one species208 Fluconazole achieves a 10 times higherconcentration in urine than in blood with powerful effect even onCglabrata infections Therefore it represents a first line treatment ofany Candida urinary tract infection

In a randomized placebo-controlled multicentre study amongpatients with asymptomatic candiduria Sobel et al209 found thatfluconazole (200 mgday) hastened the time to negative resultsof urine cultures However the rate of negative urine cultures2 weeks after the end of therapy was similar in the fluconazole-and placebo-treated groups showing the minimal utility of treat-ment in that setting Indeed asymptomatic candiduria should betreated only in high-risk situations namely patients with neutrope-nia infants with low birth weight patients with renal allografts andpatients who will undergo urologic manipulations (recommenda-tion of grade B-III from the IDSA) The optimal regimen in thatsetting is not known Short courses regimen are not recommendedand therapy for 1ndash2 weeks should be efficient

Ascending pyelonephritis treatment should also include ade-quate urinary drainage and removal of obstructive fungusballs210 Urinary tract devices should be optimally removed orat least replaced

Haematogenous renal involvement should be treated with high-dose parenteral fluconazole (6 mgkgday) in accordance with therecently published IDSA guidelines57

Fluconazole in childreninfants

No specific approval of fluconazole has been obtained inyoung children before the age of 6 months but a few studieshave evaluated its use in several settings

Prophylaxis of systemic candidiasis in neonates

Few studies have focused on the use of fluconazole as a prophy-lactic agent against invasive candidiasis in neonates Kaufmanet al211 demonstrated in 2001 the efficacy and safety of flucona-zole (3 mgkg every 3 days during the first 2 weeks then every2 days during the following 2 weeks and then every day until thesixth week of life) in extremely low birth weight and high-riskinfants (lt1000 g) in preventing both colonization and invasivefungal infection High risk was defined as the presence of a centralvascular catheter or endotracheal tube Indeed among the 50infants randomly assigned to fluconazole the rate of colonization(22) was significantly lower than in the 50 placebo-treated ones(60) no invasive fungal infection developed in the fluconazolegroup compared with a 20 rate of infection in the placebo groupNo adverse effect of fluconazole was documented

Kicklighter et al212 similarly observed the safety of fluconazoleat 6 mgkg (for 6 weeks) and its efficacy among neonates with lowbirth weight (lt1500 g) in the prevention of rectal colonization(however occurrence of invasive candidiasis was similar inboth groups) A Cochrane review of fluconazole prophylaxis inpreterm infants demonstrated a reduced risk of invasive infection(related risk 020) and mortality (related risk 044) in fluconazole-treated patients compared with placebo-treated patients213

Although concerns about resistance to azoles have been raised

the vast majority ofCandida spp strains have remained susceptibleto fluconazole over the past decade in this population40

Fluconazole in systemic candidiasis in childreninfants

Neonatal candidaemia Candidaemia is a major cause of sepsis inneonatal ICU representing up to 16 of all sepsis cases Therelated mortality rate is high often nearly 50214 Most casesare related to C albicans and C parapsilosis with a recent risein cases related to C tropicalis The main risk factors for invasivecandidiasis among neonates are low birth weight intravascularcatheters intratracheal intubation total parenteral nutrition andadministration of intralipid solution and recent administration ofbroad-spectrum antibiotics and corticosteroids10

Treatment with amphotericin B and 5-flucytosine has been thegold standard for years However amphotericin B has some seriousside effects which makes it mandatory to consider its use in thatsetting With good profile of tolerance good diffusion in all tissuesand body fluids and reliable oral absorption fluconazole has beenstudied as an alternative (see Table 15) In 1994 Fasano et al215

reported the compassionate use of fluconazole among 40 new-borns including 11 who presented with Candida sp meningitisThey were treated with a mean daily dosage of 5 mgkgday for amean duration of 26 days Of the 32 patients with evaluable out-come 31 experienced clearance of infection Other studies haveconfirmed these results in the recent years11216ndash220 In a multicen-tre prospective randomized study Driessen et al220 compared theefficacy and safety of either amphotericin B ndash 5-flucytosine orfluconazole (oral or intravenous dose of 10 mgkg as initialdose and then 5 mgkgday) in neonates with candidaemia Inthe fluconazole group 812 (67) survived versus 611 (55) inthe other group220 Among the four patients who died in the flu-conazole group two had treatment failure versus one in the ampho-tericin B group Cytolytic hepatitis was less frequent in thefluconazole-treated group Two isolated case reports also suggestthat the association of fluconazole and flucytosine might be syn-ergistic in the treatment of neonatal candidaemia222223

Very recently Mondal et al229 compared the efficacy and safetyof oral itraconazole versus oral fluconazole (both doses of 10 mgkgday) in newborns and paediatric patients with candidaemiaSimilar cure rate (81 and 82) mortality rate (95 and 135)and number of side effects were observed224 Fluconazole thusappears as a safe and effective systemic antifungal agent in thesetting of neonatal candidiasis

Children with systemic candidiasis Excluding the setting of neo-natal candidiasis very few studies have however focused on thepaediatric population when studying the efficiency of fluconazolefor the treatment of invasive candidiasis

In 1991 Viscoli et al reported the outcome of 24 immunocom-promised children treated with fluconazole (6 mgkgday) for 34episodes of proven invasive candidiasis A total of 3034 clinicaland microbiological cures were achieved Two patients with fun-gaemia due toC parapsilosis required an increase in dosage of up to12 mgkg Transient drug-related increases of liver transaminasesoccurred in two cases (6)225 In 1994 Fasano et al reported theoutcome of 63 children with AIDS cancer or transplantationprospectively receiving fluconazole as compassionate treatment(dose regimen ranging from 016 to 11 mgkgday mean 34 mgkgday)215 Half of them had fungaemia while the others hadrespiratory urinary tract or superficial oropharyngeal infections

Review

403

Clinical cure or improvement was achieved in 5263 (83) andpathogen eradication was achieved in 4359 (73)17 Huttovaet al218 reported in 1998 the outcome of 10 children withnosocomial fungal meningitis including 8 cases of candidal men-ingitis treated using fluconazole Five of them survived with clinicaland microbiological cure

Conclusions

Almost 15 years after its launch fluconazole remains a cornerstoneof antifungal prophylaxis and therapy of invasive candidiasis It hasan excellent pharmacokinetic and safety profile even in debilitatedpatients with good tissue penetration and a lack of major druginteractions particularly with immunosuppressive agents It can beprescribed in patients with renal failure if daily dosages are adaptedto the creatinine serum level Its spectrum of antimicrobial efficacyis reasonable and it remains active against most intrinsically sus-ceptible Candida spp encountered in systemic disease with lt5of C albicans resistant to fluconazole in that setting Although Ckrusei is intrinsically resistant to fluconazole it is rarely reported asa cause of systemic infection outside neutropenic patients Thus Cglabrata is the only species which might now limit the use offluconazole for the first line therapy of yeast fungaemia whenthe species is not identified Similarly patients who recentlyreceived fluconazole as antifungal prophylaxis should not be trea-ted with fluconazole for the curative treatment of a presumed orproven episode of systemic candidiasis The fungistatic effect offluconazole against Candida spp does not appear to influence theoutcome of candidaemic episodes at least in comparison withamphotericin B which is apparently fungicidal against Candidaspp Finally when summarizing its valuable properties the strongdemonstration of its efficacy in large randomized controlled trialsand selected clinical series its availability in various commercialpresentations and its current low cost fluconazole still remains aleading antifungal drug against susceptible Candida species

Transparency declarations

C C E H A L P R and F D have no conflicts to declareD W D In the past 5 years D W D has received grant supportfrom Astellas Merck Pfizer F2G OrthoBiotech Indevus Basileathe Fungal Research Trust the Wellcome Trust the National Insti-tute of Allergy and Infectious Diseases and the European Union Hehas been an advisorconsultant to Merck Basilea Vicuron (nowPfizer) Schering Plough Indevus F2G Nektar Daiichi SigmaTau Astellas PPL Therapeutics and Uriach He has been paid fortalks on behalf of Astellas Merck and Pfizer He holds foundershares in F2G Ltd and GBE Diagnostics Ltd and talks on behalf ofAstellas Merck and Gilead Sciences O L Speakers bureau forPfizer

References

1 Richardson K The discovery and profile of fluconazole J Chemo-

ther 1990 2 51ndash4

2 Richardson K Brammer KW Marriott MS et al Activity of

UK-49858 a bis-triazole derivative against experimental infections

with Candida albicans and Trichophyton mentagrophytes Antimicrob

Agents Chemother 1985 27 832ndash5

3 Vanrsquot Wout JW Mattie H van Furth R A prospective study of the

efficacyof fluconazole (UK-49858)againstdeep-seated fungal infections

J Antimicrob Chemother 1988 21 665ndash72Table

15

No

n-c

om

par

ativ

est

ud

ies

on

flu

con

azo

leas

cura

tiv

etr

eatm

ent

of

neo

nat

alca

nd

idae

mia

Ref

eren

ce

Nu

mb

ero

f

pat

ien

tsR

egim

enM

icro

bio

log

ical

cure

Sid

eef

fect

s

Dri

esse

net

al

22

02

1v

ery

low

bir

thw

eig

ht

5m

gk

gfo

r

1ndash

42

day

sm

ean

16

90

3

0

cyto

lyti

ch

epat

itis

Fas

anoet

al

21

54

05

mg

kg

for

2ndash

80

day

sm

ean

26

97

5

cy

toly

tic

hep

atit

is

Wai

ner

etal

21

61

91

0m

gk

go

nd

ay1

then

5m

gk

g

63

su

rviv

ing

32

fun

gal

free

dea

ths

NS

Hu

anget

al

21

71

8v

ery

low

bir

thw

eig

ht

3ndash

10

mg

kg

for

15

ndash1

73

day

sm

ean

34

6fi

rst

lin

etr

eatm

ent

83

13

afte

rA

MB

fail

ure

6

2

29

cy

toly

tic

hep

atit

is

Hu

tto

vaet

al

21

84

0v

ery

low

bir

thw

eig

ht

6m

gk

gfo

r6

ndash4

8d

ays

65

cu

rew

ith

ou

tre

lap

se5

cy

toly

tic

hep

atit

is

5

-ele

vat

edse

rum

crea

tin

ine

Gu

rpin

aret

al

21

92

42

ndash1

6m

gk

gfo

r

5ndash

72

day

sm

ean

25

96

8

an

aem

iao

rcy

toly

tic

hep

atit

is

Sch

war

zeet

al

11

53

5ndash

6m

gk

gfo

r3

wee

ks

mea

n2

17

8

4

cyto

lyti

ch

epat

itis

AM

B

amphote

rici

nB

ver

ylo

wbir

thw

eight

lt1500

g

NS

st

atis

tica

lly

not

signif

ican

t

Review

404

4 Vanrsquot Wout JW deGraeff-Meeder ER Paul LC et al Treatment of

two cases of cryptococcal meningitis with fluconazole Scand J Infect Dis

1988 20 193ndash8

5 Tucker RM Williams PL Arathoon EG et al Pharmacokinetics of

fluconazole in cerebrospinal fluid and serum in human coccidioidal

meningitis Antimicrob Agents Chemother 1988 32 369ndash73

6 ByrneWRWajszczukCPCryptococcalmeningitis in theacquired

immunodeficiency syndrome (AIDS) successful treatment with flucona-

zole after failure of amphotericin B Ann Intern Med 1988 108 384ndash5

7 HughesCE BeggsWH Action of fluconazole (UK-49858) in rela-

tion to other systemic antifungal azoles J Antimicrob Chemother 1987

19 171ndash4

8 DebruyneDClinicalpharmacokineticsof fluconazole insuperficial

and systemic mycoses Clin Pharmacokinet 1997 33 52ndash77

9 Brammer KW Coates PE Pharmacokinetics of fluconazole in

pediatric patients Eur J Clin Microbiol Infect Dis 1994 13 325ndash9

10 Schwarze R Penk A Pittrow L Administration of fluconazole in

children below 1 year of age Mycoses 1999 42 3ndash16

11 Schwarze R Penk A Pittrow L Treatment of candidal infections

with fluconazole in neonates and infants Eur J Med Res 2000 5 203ndash8

12 Thaler FBernardBTodMet al Fluconazolepenetration in cereb-

ral parenchyma in humans at steady stateAntimicrob Agents Chemother

1995 5 1154ndash6

13 Bozzette SA Gordon RL Yen A et al Biliary concentrations of

fluconazole in a patient with candidal cholecystitis case reportClin Infect

Dis 1992 4 701ndash3

14 Debruyne D Ryckelynck JP Moulin M et al Pharmacokinetics of

fluconazole in patients undergoing continuous ambulatory peritoneal dial-

ysis Clin Pharmacokinet 1990 18 491ndash8

15 Tod M Lortholary O Padoin C et al Intravenous penetration of

fluconazole during endophthalmitis Clin Microbiol Infect 1997 3 143ndash4

16 Urbak SF Degn T Fluconazole in the management of fungal ocu-

lar infections Ophthalmologica 1994 3 147ndash56

17 Fasano C OrsquoKeefe J Gibbs D Fluconazole treatment of children

with severe fungal infections not treatable with conventional agentsEur J

Clin Microbiol Infect Dis 1994 13 344ndash7

18 Aleck KA Bartley DL Multiple malformation syndrome following

fluconazole use in pregnancy report of an additional patient Am J Med

Genet 1997 72 253ndash6

19 Buijk SL Gyssens IC Mouton JW et al Pharmacokinetics of

sequential intravenous and enteral fluconazole in critically ill surgical

patients with invasive mycoses and compromised gastro-intestinal func-

tion Intensive Care Med 2001 27 115ndash21

20 El-Yazigi AEllisMErnstPet al Pharmacokinetics of oral flucona-

zole when used for prophylaxis in bone marrow transplant recipients

Antimicrob Agents Chemother 1997 41 914ndash17

21 Finch CK Green CA Self TH Fluconazole-carbamazepine inter-

action South Med J 2002 95 1099ndash100

22 Tucker RM Denning DW Hanson RH et al Interaction of azoles

with rifampin phenytoin and carbamazepine in vitro and clinical obser-

vations Clin Infect Dis 1992 14 165ndash74

23 Stockley IH Stockleyrsquos Drug Interactions A Source Book of Inter-

actions Their Mechanisms Clinical Importance and Management 6th

edn London UK Pharmaceutical Press 2002

24 von Moltke LL Greenblatt DJ Duan SX et al Inhibition of terfena-

dine metabolism in vitro by azole antifungal agents and by selective sero-

tonin reuptake inhibitor antidepressants relation to pharmacokinetic

interactions in vivo J Clin Psychopharmacol 1996 16 104ndash12

25 BrockmeyerNH Tillmann I Mertins L et al Pharmacokinetic inter-

action of fluconazole and zidovudine in HIV-positive patients Eur J Med

Res 1997 2 377ndash83

26 van Burik JA LeisenringW Myerson D et al The effect of prophy-

lactic fluconazole on the clinical spectrum of fungal diseases in bone

marrow transplant recipients with special attention to hepatic candidiasis

An autopsy study of 355 patients Medicine 1998 77 246ndash54

27 Wingard JR Antifungal chemoprophylaxis after blood andmarrow

transplantation Clin Infect Dis 2002 34 1386ndash90

28 GarbinoJLewDPRomandJAetalPreventionofsevereCandida

infections in nonneutropenic high-risk critically ill patients a randomized

double-blind placebo-controlled trial in patients treatedbyselectivediges-

tive decontamination Intensive Care Med 2002 28 1708ndash17

29 Gearhart MO Worsening of liver function with fluconazole and

review of azole antifungal hepatotoxicity Ann Pharmacother 1994 281177ndash81

30 Crerar-Gilbert A Boots R Fraenkel D et al Survival following ful-

minant hepatic failure from fluconazole induced hepatitis Anaesth Inten-

sive Care 1999 27 650ndash2

31 PappasPGKauffmanCAPerfect Jetal Alopeciaassociatedwith

fluconazole therapy Ann Intern Med 1995 123 354ndash7

32 Stevens DA Diaz M Negroni R et al Safety evaluation of chronic

fluconazole therapy Fluconazole Pan-American Study Group

Chemotherapy 1997 5 371ndash7

33 Anaissie EJ Kontoyiannis DP Huls C et al Safety plasma con-

centrations and efficacy of high-dose fluconazole in invasive mold infec-

tions J Infect Dis 1995 172 599ndash602

34 Gussenhoven MJ Haak A Peereboom-Wynia JD et al Stevens-

Johnson syndrome after fluconazole Lancet 1991 338 120

35 NovelliVHolzelHSafetyand tolerabilityof fluconazole inchildrenAntimicrob Agents Chemother 1999 43 1955ndash60

36 Koks CH Crommentuyn KM Hoetelmans RM et al Can

fluconazole concentrations in saliva be used for therapeutic drug mon-

itoring Ther Drug Monit 2001 4 449ndash53

37 Louie A Drusano GL Banerjee P et al Pharmacodynamics of

fluconazole in amurinemodel of systemic candidiasisAntimicrob Agents

Chemother 1998 42 1105ndash9

38 PittrowLPenkAPlasmaand tissueconcentrationsof fluconazole

and their correlation to breakpoints Mycoses 1997 40 25ndash32

39 Rex JH Pfaller MA Galgiani JN et al Development of interpretive

breakpoints forantifungalsusceptibility testing conceptual frameworkand

analysis of in vitro-in vivo correlation data for fluconazole itraconazole

and Candida infections Subcommittee on Antifungal Susceptibility Test-

ingof theNationalCommittee forClinical LaboratoryStandardsClin Infect

Dis 1997 24 235ndash47

40 Pfaller MA Diekema DJ Twelve years of fluconazole in clinical

practiceglobal trends inspeciesdistributionand fluconazolesusceptibility

of bloodstream isolatesofCandida International FungalSurveillancePar-

ticipant Group Clin Microbiol Infect 2004 10 Suppl 1 11ndash23

41 Tortorano AM Rigoni AL Biraghi E et al The European Confed-

eration of Medical Mycology (ECMM) survey of candidaemia in Italy anti-

fungal susceptibility patterns of 261 non-albicans Candida isolates from

blood J Antimicrob Chemother 2003 52 679ndash82

42 Pfaller MAMesser SA Boyken L et al Geographic variation in the

susceptibilities of invasive isolates of Candida glabrata to seven systemi-

cally active antifungal agents a global assessment from the ARTEMIS

Antifungal Surveillance Program conducted in 2001 and 2002 J Clin

Microbiol 2004 42 3142ndash6

43 Paya CV Fungal infections in solid-organ transplantation Clin

Infect Dis 1993 16 677ndash88

44 Singh N Wagener MM Marino IR et al Trends in invasive fungal

infections in liver transplant recipients correlation with evolution in trans-

plantation practices Transplantation 2002 73 63ndash7

45 Fung JJ Fungal infection in liver transplantation Transplant InfectDis 2002 4 18ndash23

46 Winston DJ Pakrasi A Busuttil RW Prophylactic fluconazole in

liver transplant recipientsA randomized double-blind placebo-controlled

trial Ann Intern Med 1999 131 729ndash37

47 Gladdy RA Richardson SE Davies HD et al Candida infection in

pediatric liver transplant recipients Liver Transpl Surg 1999 5 16ndash24

Review

405

48 Castaldo P Stratta RJ Wood RP et al Clinical spectrum of fungal

infections after orthotopic liver transplantation Arch Surg 1991 126149ndash56

49 Husain S Tollemar J Dominguez EA et al Changes in the spec-

trum and risk factors for invasive candidiasis in liver transplant recipients

prospective multicenter case-controlled study Transplantation 2003

75 2023ndash9

50 GeorgeMJ Snydman DRWerner BG et al The independent role

of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic

liver transplant recipients Boston Center for Liver Transplantation

CMVIG-Study Group Cytogam MedImmune Inc Gaithersburg Mary-

land Am J Med 1997 103 106ndash13

51 Dockrell DH Mendez JC Jones M et al Human herpesvirus 6

seronegativity before transplantation predicts the occurrence of fungal

infection in liver transplant recipientsTransplantation 1999 67 399ndash403

52 Tollemar J Ericzon BG Barkholt L et al Risk factors for deep

Candida infections in liver transplant recipients Transplant Proc 1990

22 1826ndash7

53 Lumbreras C Cuervas-Mons V Jara P et al Randomized trial of

fluconazole versus nystatin for the prophylaxis of Candida infection

following liver transplantation J Infect Dis 1996 174 583ndash8

54 Winston DJ Busuttil RW Randomized controlled trial of oral itra-

conazole solution versus intravenousoral fluconazole for prevention of

fungal infections in liver transplant recipients Transplantation 2002

74 688ndash95

55 Tortorano AM Viviani MA PaganoA et al Candida colonization in

orthotopic liver tranplantation fuconazole versus oral amphoericin B

J Mycol Med 1995 5 21ndash4

56 Kung N Fisher N Gunson B et al Fluconazole prophylaxis for

high-risk liver transplant recipients Lancet 1995 345 1234ndash5

57 Pappas PG Rex JH Sobel JD et al Guidelines for treatment of

candidiasis Clin Infect Dis 2004 38 161ndash89

58 PayaCV Prevention of fungal infection in transplantation TransplInfect Dis 2002 4 S46ndash51

59 LortholaryO Dupont B Antifungal prophylaxis during neutropenia

and immunodeficiency Clin Microbiol Rev 1997 10 477ndash504

60 Benedetti E Gruessner AC Troppmann C et al Intra-abdominal

fungal infections after pancreatic transplantation incidence treatment

and outcome J Am Coll Surg 1996 183 307ndash16

61 LumbrerasC Fernandez I Velosa J et al Infectious complications

following pancreatic transplantation incidence microbiological and clini-

cal characteristics and outcome Clin Infect Dis 1995 20 514ndash20

62 Patterson JE Epidemiology of fungal infections in solid organ

transplant patients Transpl Infect Dis 1999 1 229ndash36

63 Kusne S Furukawa H Abu-Elmagd K et al Infectious complica-

tions after small bowel transplantation in adults an update Transplant

Proc 1996 28 2761ndash2

64 Paterson DL Ndirangu M Kwak EJ et al Opportunistic infections

in solid-organ transplant recipients pre-treated with alumetuzumab In

Abstracts of the Forty-Fourth Interscience Conference on Antimicrobial

Agents and Chemotherapy Washington DC 2004 Abstract K-1427 p

357 American Society for Microbiology Washington DC USA

65 Kramer MR Marshall SE Starnes VA et al Infectious complica-

tions in heart-lung transplantation Analysis of 200 episodes Arch Intern

Med 1993 153 2010ndash6

66 Goodrich JMReedECMori M et al Clinical features and analysis

of risk factors for invasive candidal infection after marrow transplantation

J Infect Dis 1991 164 731ndash40

67 Dykewicz CA Centers for Disease Control and Prevention (US)

Infectious Diseases Society of America American Society of Blood and

MarrowTransplantation Summary of the guidelines for preventing oppor-

tunistic infections among hematopoietic stem cell transplant recipients

Clin Infect Dis 2001 33 139ndash44

68 Sable CA Donowitz GR Infections in bone marrow transplant

recipients Clin Infect Dis 1994 18 273ndash81

69 Goodman JLWinston DJ Greenfield RA et al A controlled trial of

fluconazole to prevent fungal infections in patients undergoing bone mar-

row transplantation N Engl J Med 1992 326 845ndash51

70 Slavin MA Osborne B Adams R et al Efficacy and safety of flu-

conazole prophylaxis for fungal infectionsaftermarrow transplantationmdasha

prospective randomized double-blind study J Infect Dis 1995 1711545ndash52

71 Marr KA Seidel K SlavinMA et al Prolonged fluconazole prophy-

laxis is associated with persistent protection against candidiasis-related

death in allogeneic marrow transplant recipients long-term follow-up of a

randomized placebo-controlled trial Blood 2000 96 2055ndash61

72 AlangadenGChandrasekar PH BaileyE et al Antifungal prophy-

laxis with low-dose fluconazole during bone marrow transplantation The

Bone Marrow Transplantation Team Bone Marrow Transplant 1994 14919ndash24

73 Wolff SN Fay J Stevens D et al Fluconazole versus low-dose

amphotericin B for the prevention of fungal infections in patients under-

going bonemarrow transplantation a study of theNorthAmericanMarrow

Transplant Group Bone Marrow Transplant 2000 25 853ndash9

74 Annaloro C Oriana A Tagliaferri E et al Efficacy of different pro-

phylactic antifungal regimens in bone marrow transplantation Haemato-

logica 1995 80 512ndash17

75 Winston DJ Maziarz RT Chandrasekar PH et al Intravenous and

oral itraconazole versus intravenous and oral fluconazole for long-term

antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant

recipients A multicenter randomized trial Ann Intern Med 2003 138705ndash13

76 MarrKACrippaF LeisenringWet al Itraconazoleversus flucona-

zole forpreventionof fungal infections inpatients receivingallogeneicstem

cell transplants Blood 2004 103 1527ndash33

77 MacMillan ML Goodman JL DeFor TE et al Fluconazole to pre-

vent yeast infections in bone marrow transplantation patients a random-

ized trial of high versus reduced dose and determination of the value of

maintenance therapy Am J Med 2002 112 369ndash79

78 Marr KA Seidel K White TC et al Candidemia in allogeneic blood

and marrow transplant recipients evolution of risk factors after the adop-

tion of prophylactic fluconazole J Infect Dis 2000 181 309ndash16

79 van Burik JA Ratanatharathorn V Stepan DE et al Micafungin

versus fluconazole for prophylaxis against invasive fungal infections dur-

ing neutropenia in patients undergoing hematopoietic stem cell trans-

plantation Clin Infect Dis 2004 39 1407ndash16

80 Prentice HG Kibbler CC Prentice AG Towards a targeted risk-

based antifungal strategy in neutropenic patients Br J Haematol 2000

110 273ndash84

81 Laverdiere M Rotstein C Bow EJ et al Impact of fluconazole

prophylaxis on fungal colonizatin and infection rates in neutropenic

patients The Canadian Fluconazole Study J Animicrob Chemother

2000 46 1001ndash8

82 Winston DJ Chandrasekar PH Lazarus HM et al Fluconazole

prophylaxis of fungal infections in patients with acute leukemia Results

of a randomized placebo-controlled double-blind multicenter trial Ann

Intern Med 1993 118 495ndash503

83 Chandrasekar PHGatnyCMEffect of fluconazole prophylaxis on

fever and use of amphotericin in neutropenic cancer patients Bone Mar-

row Transplantation Team Chemotherapy 1994 40 136ndash43

84 Rotstein C Bow EJ Laverdiere M et al Randomized placebo-

controlled trial of fluconazole prophylaxis for neutropenic cancer patients

benefit basedonpurposeand intensity of cytotoxic therapy TheCanadian

Fluconazole Prophylaxis Study Group Clin Infect Dis 1999 28 331ndash40

85 YamacK Senol E HaznedarR Prophylactic use of fluconazole in

neutropenic cancer patients Postgrad Med J 1997 71 284ndash6

86 KernW BehreG Rudolf T et al Failure of fluconazole prophylaxis

to reducemortality or the requirement of systemic amphotericin B therapy

during treatment for refractory acute myeloid leukemia results of a

Review

406

prospective randomized phase III study German AML Cooperative

Group Cancer 1998 83 291ndash301

87 SchaffnerA SchaffnerM Effect of prophylactic fluconazole on the

frequencyof fungal infectionsamphotericinBuseandhealthcarecosts in

patients undergoing intensive chemotherapy for hematologic neoplasias

J Infect Dis 1995 172 1035ndash41

88 Egger T Gratwohl A Tichelli A et al Comparison of fluconazole

with oral polyenes in the prevention of fungal infections in neutropenic

patients A prospective randomized single-center study Support Care

Cancer 1995 3 139ndash46

89 Morgenstern GR Prentice AG Prentice H et al A randomized

controlled trial of itraconazole versus fluconazole for the prevention of

fungal infections in patients with haematological malignancies UK Mul-

ticentre Antifungal Prophylaxis Study Group Br J Haematol 1999 105901ndash11

90 EllisMEClinkHErnstPetalControlledstudyof fluconazole in the

preventionof fungal infections in neutropenic patientswith haematological

malignancies and bone marrow transplant recipients Eur J Clin Microbiol

Infect Dis 1994 13 3ndash11

91 Philpott-Howard JN Wade JJ Mufti GJ et al Randomized com-

parisonoforal fluconazoleversusoralpolyenes for thepreventionof fungal

infection in patients at risk of neutropenia Multicentre Study Group

J Antimicrob Chemother 1993 31 973ndash84

92 Ninane J A multicentre study of fluconazole versus oral polyenes

in the prevention of fungal infection in children with hematological or

oncological malignancies Multicentre Study Group Eur J Clin Microbiol

Infect Dis 1994 13 330ndash7

93 Menichetti F Del Favero A Martino P et al Preventing fungal

infection in neutropenic patients with acute leukemia fluconazole com-

pared with oral amphotericin B The GIMEMA Infection Program Ann

Intern Med 1994 120 913ndash18

94 Akiyama H Mori S Tanikawa S et al Fluconazole versus oral

amphotericin B in preventing fungal infection in chemotherapy-induced

neutropenic patients with haematological malignancies Mycoses 1996

36 373ndash8

95 Meunier F AounM JanssensM et al Chemoprophylaxis of fungal

infections in granulocytopenic patients using fluconazole versus oral

amphotericin B Drug Invest 1991 3 258ndash65

96 Rozenberg-Arska M Dekker AW Branger J et al A randomized

study to compare oral fluconazole to amphotericin B in the prevention of

fungal infections inpatientswithacute leukaemiaJAntimicrobChemother

1991 27 369ndash76

97 Brammer KW Management of fungal infection in neutropenic

patients with fluconazole Haematol Blood Transfus 1990 33 546ndash50

98 Bodey GP Anaissie EJ Elting LS et al Antifungal prophylaxis

during remission induction therapy for acute leukemia fluconazole versus

intravenous amphotericin B Cancer 1994 73 2099ndash106

99 Kanda Y Yamamoto R Chizuka A et al Prophylactic action of

oral fluconazole against fungal infection in neutropenic patients A

meta-analysis of 16 randomized controlled trials Cancer 2000 891611ndash25

100 Bow EJ Laverdiere M Lussier N et al Antifungal prophylaxis for

severely neutropenic chemotherapy recipients a meta analysis of

randomized-controlled clinical trials Cancer 2002 94 3230ndash46

101 Viscoli C Paesmans M Sanz M et al Association between

antifungal prophylaxis and rate of documented bacteremia in febrile

neutropenic cancer patients Clin Infect Dis 2001 32 1532ndash7

102 HughesWT Armstrong D BodeyGP et al 2002 guidelines for the

use of antimicrobial agents in neutropenic patients with cancerClin Infect

Dis 2002 34 730ndash51

103 Cornely OA Bohme A Buchheidt D et al Prophylaxis of invasive

fungal infections in patients with hematological malignancies and solid

tumorsmdashguidelines of the Infectious Diseases Working Party (AGIHO)

of the German Society of Hematology and Oncology (DGHO) Ann

Hematol 2003 82 Suppl 2 186ndash200

104 McNeil MM Nash SL Hajjeh RA et al Trends in mortality due to

invasivemycotic diseases in theUnitedStates 1980ndash1997Clin InfectDis

2001 33 641ndash7

105 KibblerCCSeatonSBarnesRA et alManagement and outcome

of bloodstream infections due to Candida species in England and Wales

J Hosp Infect 2003 54 18ndash24

106 Marchetti O Bille J Fluckiger U et al Fungal Infection Network of

Switzerland Epidemiology of candidemia in Swiss tertiary care hospitals

secular trends 1991-2000 Clin Infect Dis 2004 38 311ndash20

107 Gudlaugsson O Gillespie S Lee K et al Attributable mortality of

nosocomial candidemia revisited Clin Infect Dis 2003 37 1172ndash7

108 Ibanez-Nolla J Nolla-Salas M Leon MA et al Early diagnosis of

candidiasis in nonneutropenic critically ill patients J Infect 2004 48181ndash92

109 BlumbergHMJarvisWRSoucieJMetalRisk factors for candidal

bloodstream infections in surgical intensive care unit patients the NEMIS

prospective multicenter study The National Epidemiology of Mycosis

Survey Clin Infect Dis 2001 33 177ndash86

110 Pittet D Monod M Suter PM et al Candida colonization and

subsequent infections in critically ill surgical patients Ann Surg 1994

220 751ndash8

111 Sendid B Poirot JL Tabouret M et al Combined detection of

mannanaemia and antimannan antibodies as a strategy for the diagnosis

of systemic infectioncausedbypathogenicCandidaspeciesJMedMicro-

biol 2002 51 433ndash42

112 Bar W Hecker H Diagnosis of systemic Candida infections in

patients of the intensive care unit Significance of serum antigens and

antibodies Mycoses 2002 45 22ndash8

113 Calandra T Marchetti O Clinical trials of antifungal prophy-

laxis among patients undergoing surgery Clin Infect Dis 2004 39S185ndash92

114 Sypula WT Kale-Pradhan PB Therapeutic dilemma of flucona-

zole prophylaxis in intensive care Ann Pharmacother 2002 36 155ndash9

115 Pelz RK Hendrix CW Swoboda SM et al Double-blind placebo-

controlled trial of fluconazole to prevent candidal infections in critically ill

surgical patients Ann Surg 2001 233 542ndash8

116 Eggimann P Francioli P Bille J et al Fluconazole prophylaxis

prevents intraabdominal candidiasis in high-risk surgical patients Crit

Care Med 1997 27 1066ndash72

117 Swoboda SM Merz WG Lipsetta PA Candidemia the impact of

antifungal prophylaxis in a surgical intensive care unitSurg Infect20034345ndash54

118 Todd JC OrsquoNeal VG Grady KP et al Reduction of secondary

mycotic infections in the trauma intensivie care unit with fluconazole

J Trauma 1991 31 1722ndash27

119 Jacobs S Price Evans DA Tariq M et al Fluconazole improves

survival in septic shock a randomized double-blind prospective studyCrit

Care Med 2003 31 1938ndash46

120 Zervos EE Fink GW Norman JG et al Fluconazole increases

bactericidal activity of neutrophils through non-cytokine-mediated path-

way J Trauma 1996 41 465ndash70

121 AblesAZBlumerNAValainisGTetal Fluconazoleprophylaxis of

severe Candida infection in trauma and postsurgical patients a prospec-

tive double-blind randomised placebo-controlled trial Infect Dis Clin

Pract 2000 9 169ndash75

122 Kam LW Lin JD Management of systemic candidal infections in

the intensive care unit Am J Health Syst Pharm 2002 59 33ndash41

123 Rocco TR Reinert SE Simms HH Effects of fluconazole admin-

istration in critically ill patients analysis of bacterial and fungal resistance

Arch Surg 2000 135 160ndash5

124 Tortorano AM Caspani L Rigoni AL et al Candidosis in the inten-

sive care unit a 20-year survey J Hosp Infect 2004 57 8ndash13

125 EggimannPGarbino J Pittet DManagement ofCandida species

infections in critically ill patients Lancet Infect Dis 2003 3 772ndash85

Review

407

126 EggimannPGarbinoJPittetDEpidemiologyofCandida species

infections incritically ill non-immunosuppressedpatientsLancet InfectDis

2003 3 685ndash702

127 Martins MD Lozano-Chiu M Rex JH Declining rates of oropha-

ryngeal candidiasis and carriage of Candida albicans associated with

trends toward reduced rates of carriage of fluconazole-resistant C albi-

cans in human immunodeficiency virus-infected patients Clin Infect Dis

1998 27 1291ndash4

128 Powderly WG Finkelstein D Feinberg J et al A randomized trial

comparing fluconazole with clotrimazole troches for the prevention of fun-

gal infections in patients with advanced human immunodeficiency virus

infection NIAID AIDS Clinical Trials Group N Engl J Med 1995 332700ndash5

129 Leen CL Dunbar EM Ellis ME et al Once-weekly fluconazole to

prevent recurrenceof oropharyngeal candidiasis inpatientswithAIDSand

AIDS-related complex a double-blind placebo-controlled study J Infect

1990 21 55ndash60

130 Stevens DA Greene SI Lang OS Thrush can be prevented in

patients with acquired immunodeficiency syndrome and the acquired

immunodeficiency syndrome-related complex Randomized double-

blind placebo-controlled study of 100-mg oral fluconazole daily Arch

Intern Med 1991 151 2458ndash64

131 Just-Nubling G Gentschew G Meissner K Fluconazole prophy-

laxis of recurrent oral candidiasis inHIV-positive patientsEur JClinMicro-

biol Infect Dis 1991 10 917ndash21

132 Marriott DJ Jones PD Hoy JF et al Fluconazole once a week as

secondary prophylaxis against oropharyngeal candidiasis in HIV-infected

patients A double-blind placebo-controlled studyMed J Aust 1993 158312ndash16

133 Schuman P Capps L Peng G et al Weekly fluconazole for the

prevention ofmucosal candidiasis inwomenwithHIV infection A random-

ized double-blind placebo-controlled trial Terry Beirn Community Pro-

grams for Clinical Research on AIDSAnn InternMed 1997 126 689ndash96

134 Havlir DV DubeMPMcCutchan JA et al Prophylaxis with weekly

versus daily fluconazole for fungal infections in patients with AIDS Clin

Infect Dis 1998 27 1369ndash75

135 Pagani JL Chave JP Casjka C et al Efficacy tolerability and

development of resistance in HIV-positive patients treated with flucona-

zole for secondary prevention of oropharyngeal candidiasis a random-

ized double-blind placebo-controlled trial JAntimicrobChemother 2002

50 231ndash40

136 Vazquez JA Peng G Sobel JD et al Evolution of antifungal sus-

ceptibility amongCandidaspecies isolates recovered fromhuman immun-

odeficiency virus-infected women receiving fluconazole prophylaxis Clin

Infect Dis 2001 33 1069ndash75

137 Delfraissy JF Prise en charge therapeutique des patients infectespas le VIH Rapport Delfraissy Paris Flammarion 2004

138 DePauwBERaemaekers JMDonnelly JPet al Anopenstudyon

the safety and efficacy of fluconazole in the treatment of disseminated

Candida infections in patients treated for hematological malignancy Ann

Hematol 1995 70 83ndash7

139 Anaissie EJ Vartivarian SE Abi-Said D et al Fluconazole versus

amphotericin B in the treatment of hematogenous candidiasis a matched

cohort study Am J Med 1996 101 170ndash6

140 Anaissie EJ Darouiche RO Abi-Said D et al Management of

invasive candidal infections results of a prospective randomized multi-

center study of fluconazole versus amphotericin B and review of the

literature Clin Infect Dis 1996 23 964ndash72

141 Myoken Y Kyo T Kohara T et al Breakthrough fungemia caused

by azole-resistant Candida albicans in neutropenic patients with acute

leukemia Clin Infect Dis 2003 36 1496ndash7

142 Anttila VJ FarkkilaM JanssonSE et al Diagnostic laparoscopy in

patientswith acute leukemiaandsuspectedhepatic candidiasisEur JClin

Microbiol Infect Dis 1997 16 637ndash43

143 Anaissie E Bodey GP Kantarjian H et al Fluconazole therapy for

chronic disseminated candidiasis in patients with leukemia and prior

amphotericin B therapy Am J Med 1991 91 142ndash50

144 KauffmanCA BradleySFRossSC et al Hepatosplenic candidia-

sis successful treatment with fluconazole Am J Med 1991 91 137ndash41

145 Kontoyiannis DP Luna MA Samuels BI et al Hepatosplenic can-

didiasis A manifestation of chronic disseminated candidiasis Infect Dis

Clin North Am 2000 14 721ndash39

146 Graninger W Presteril E Schneeweiss B et al Treatment of

Candida albicans fungaemia with fluconazole J Infect 1993 26 133ndash46

147 Phillips P Shafran S Garber G et al Multicenter randomized trial

of fluconazole versus amphotericin B for treatment of candidemia in

non-neutropenic patients Canadian Candidemia Study Group Eur J

Clin Microbiol Infect Dis 1997 16 337ndash45

148 Rex JH Bennett JE Sugar AM et alA randomized trial comparing

fluconazolewithamphotericinB for the treatmentof candidemia inpatients

without neutropenia Candidemia Study Group and the National Institute

N Engl J Med 1994 331 1325ndash30

149 Abele-Horn M Kopp A Sternberg U et al A randomized study

comparing fluconazolewith amphotericinB5-flucytosine for the treatment

of systemic Candida infections in intensive care patients Infection 1996

24 426ndash32

150 Nguyen MH Peacock JE Jr Tanner DC et al Therapeutic

approaches in patients with candidemia Evaluation in a multicenter

prospective observational study Arch Intern Med 1995 155 2429ndash35

151 Rex JH Pappas PG Karchmer AW et al A randomized and

blinded multicenter trial of high-dose fluconazole plus placebo versus flu-

conazole plus amphotericin B as therapy for candidemia and its con-

sequences in non-neutropenic subjectsClin Infect Dis 2003 36 1221ndash8

152 Mora-Duarte J Betts R Rotstein C et al Comparison of

caspofungin and amphotericin B for invasive candidiasis N Engl J Med

2002 347 2020ndash9

153 Sugar AM Saunders C Diamond RD et al Successful treatment

of Candida osteomyelitis with fluconazole A noncomparative study of

two patients Diagn Microbiol Infect Dis 1990 13 517ndash20

154 Tang C Successful treatment of Candida albicans osteomyelitis

with fluconazole J Infect 1993 26 89ndash92

155 LafontAOliveAGelmanMet alCandidaalbicansspondylodisci-

tis and vertebral osteomyelitis in patients with intravenous heroin drug

addiction Report of 3 new cases J Rheumatol 1994 21 953ndash6

156 Hennequin C Bouree P Hiesse C et al Spondylodiskitis due to

Candida albicans report of two patients who were successfully treated

with fluconazole and review of the literature Clin Infect Dis 1996 23176ndash8

157 Jonnalagadda S VeerabaguMP Rakela J et alCandida albicans

osteomyelitis in a liver transplant recipient a case report and review of the

literature Transplantation 1996 62 1182ndash4

158 Rossel P Schonheyder HC Nielsen H Fluconazole therapy

inCandidaalbicansspondylodiscitisScandJ InfectDis199830 527ndash30

159 TurnerDLJohnsonSARuleSASuccessful treatmentof candidal

osteomyelitis with fluconazole following failure with liposomal ampho-

tericin B J Infect 1999 38 51ndash3

160 El-Zaatari MM Hulten K Fares Y et al Successful treatment of

Candida albicans osteomyelitis of the spine with fluconazole and surgical

debridement case report J Chemother 2002 14 627ndash30

161 Seravalli L Van Linthoudt D Bernet C et al Candida glabrata

spinal osteomyelitis involving two contiguous lumbar vertebrae a case

report and review of the literature Diagn Microbiol Infect Dis 2003 45137ndash41

162 Garbino J Schnyder I LewDP et al An unusual cause of vertebral

osteomyelitis Candida species Scand J Infect Dis 2003 35 288ndash91

163 TunkelARThomasCYWispelweyBCandidaprostheticarthritis

report of a case treated with fluconazole and review of the literature Am J

Med 1993 94 100ndash3

Review

408

164 CushingRD FulgenziWR Synovial fluid levels of fluconazole in a

patient with Candida parapsilosis prosthetic joint infection who had an

excellent clinical response J Arthroplasty 1997 12 950

165 Fukasawa N Shirakura K Candida arthritis after total knee

arthroplastymdasha case of successful treatment without prosthesis removal

Acta Orthop Scand 1997 68 306ndash7

166 Lerch K Kalteis T Schubert T et al Prosthetic joint infections with

osteomyelitis due to Candida albicans Mycoses 2003 46 462ndash6

167 Clancy CJ Nguyen MH Morris AJ Candidal mediastinitis an

emerging clinical entity Clin Infect Dis 1997 25 608ndash13

168 PetrikkosGSkiadaA SabatakouH et al Case report Successful

treatment of two cases of post-surgical sternal osteomyelitis due to

Candida krusei and Candida albicans respectively with high doses of

triazoles (fluconazole itraconazole) Mycoses 2001 44 422ndash5

169 Weers-Pothoff GHavermans JF Kamphuis J et alCandida tropi-

calis arthritis in a patient with acutemyeloid leukemia successfully treated

with fluconazole case report and review of the literature Infection 1997

25 109ndash11

170 Laatikainen L TuominenM vonDickhoff K Treatment of endoge-

nous fungal endophthalmitis with systemic fluconazole with or without

vitrectomy Am J Ophthalmol 1992 113 205ndash7

171 Borne MJ Elliott JH OrsquoDay DM Ocular fluconazole treatment of

Candidaparapsilosisendophthalmitis after failed intravitreal amphotericin

B Arch Ophthalmol 1993 111 1326ndash7

172 Zarbin MA Becker E Witcher J et al Treatment of presumed

fungal endophthalmitis with oral fluconazole Ophthalmic Surg Lasers

1996 27 628ndash31

173 WongVK TasmanWEagleRC et al BilateralCandida parapsilo-

sis endophthalmitis Arch Ophthalmol 1997 115 670ndash2

174 Kauffman CA Bradley SF Vine AK Candida endophthalmitis

associated with intraocular lens implantation efficacy of fluconazole ther-

apy Mycoses 1993 36 13ndash17

175 del Palacio A Cuetara MS Ferro M et al Fluconazole in the man-

agement of endophthalmitis in disseminated candidosis of heroin addicts

Mycoses 1993 36 193ndash9

176 Luttrull JK Wan WL Kubak BM et al Treatment of ocular fungal

infections with oral fluconazole Am J Ophthalmol 1995 119 477ndash81

177 Akler ME Vellend H McNeely DM et al Use of fluconazole in the

treatment of candidal endophthalmitis Clin Infect Dis 1995 20 657ndash64

178 Christmas NJ Smiddy WE Vitrectomy and systemic fluconazole

for treatment of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1996 27 1012ndash18

179 EssmanTFFlynnHWSmiddyWEet al Treatment outcomes in a

10-year study of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1997 28 185ndash94

180 Martinez-Vazquez C Fernandez-Ulloa J Bordon J et al Candida

albicans endophthalmitis in brown heroin addicts response to early vit-

rectomyprecededand followedbyantifungal therapyClin InfectDis1998

27 1130ndash3

181 Aleixo MJ Caldeira L Ferreira ML Candida albicans meningitis

clinical case J Infect 2000 40 191ndash2

182 InoueY YozuR Ueda T et al A case report ofCandida parapsilo-

sis endocarditis J Heart Valve Dis 1998 7 240ndash2

183 Isalska BJ Stanbridge TN Fluconazole in the treatment of candi-

dal prosthetic valve endocarditis BMJ 1988 297 178ndash9

184 Martino P Meloni G Cassone A Candidal endocarditis and treat-

ment with fluconazole and granulocyte-macrophage colony-stimulating

factor Ann Intern Med 1990 112 966ndash7

185 Roupie E Darmon JY Brochard L et al Fluconazole therapy of

candidal native valveendocarditisEur JClinMicrobiol InfectDis199110458ndash9

186 Hernandez JA Gonzalez-Moreno M Llibre JM et al Candidal

mitral endocarditis and long-term treatment with fluconazole in a patient

with human immunodeficiency virus infection Clin Infect Dis 1992 151062ndash3

187 Venditti MDeBernardis FMicozzi A et al Fluconazole treatment

of catheter-related right-sided endocarditis caused by Candida albicans

and associated with endophthalmitis and folliculitis Clin Infect Dis 1992

14 422ndash6

188 Wallbridge DR McCartney AC Richardson MD Fluconazole in

the treatment ofCandidaprosthetic valveendocarditisMycoses199336259ndash61

189 Otaki M Kitamura N Candida prosthetic valve endocarditis An

autopsy review Int Surg 1993 78 252ndash3

190 Czwerwiec FS Bilsker MS Kamerman ML et al Long-term sur-

vival after fluconazole therapy of candidal prosthetic valve endocarditis

Am J Med 1993 94 545ndash6

191 Thakur RK Skelcy KM Kahn RN et al Successful treatment of

Candida prosthetic valve endocarditis with a combination of fluconazole

and amphotericin B Crit Care Med 1994 22 712ndash14

192 Cancelas JA Lopez JCabezudoE et al Native valve endocarditis

due toCandida parapsilosis a late complication after bonemarrow trans-

plantation-related fungemia Bone Marrow Transplant 1994 13 333ndash4

193 Zahid MA Klotz SA Hinthorn DR Medical treatment of recurrent

candidemia in a patient with probable Candida parapsilosis prosthetic

valve endocarditis Chest 1994 105 1597ndash8

194 Wells CJ Leech G Lever AM et al Treatment of native valve

Candida endocarditis with fluconazole J Infect 1995 31 233ndash5

195 Gilbert HM Peters ED Lang SJ et al Successful treatment of

fungal prosthetic valve endocarditis case report and review Clin Infect

Dis 1996 22 348ndash54

196 Nguyen MH Nguyen ML Yu VL et al Candida prosthetic valve

endocarditis prospective study of six cases and review of the literature

Clin Infect Dis 1996 22 262ndash7

197 Lejko-Zupanc T Kozelj M A case of recurrent Candida parapsilo-

sis prosthetic valve endocarditis cure bymedical treatment alone J Infect

1997 35 81ndash2

198 Joly V BelmatougN Leperre A et al Pacemaker endocarditis due

to Candida albicans case report and review Clin Infect Dis 1997 251359ndash62

199 Rex JH Walsh T Sobel JD et al Practice guidelines for the treat-

mentof candidiasis InfectiousDiseasesSocietyofAmericaClin InfectDis

2000 30 662ndash78

200 Baddour LM Long-term suppressive therapy for Candida para-

psilosis-induced prosthetic valve endocarditis Mayo Clin Proc 1995

70 773ndash5

201 Melgar GR Nasser RM Gordon SM Fungal prosthetic valve

endocarditis in 16 patients An 11-year experience in a tertiary care hos-

pital Medicine 1997 76 94ndash103

202 Dupont H Paugam-Burtz C Muller-Serieys C et al Predictive

factors of mortality due to polymicrobial peritonitis with Candida isolation

in peritoneal fluid in critically ill patients Arch Surg 2002 137 1341ndash6

203 Lee SC FungCP ChenHY et alCandida peritonitis due to peptic

ulcer perforation incidence rate risk factors prognosis and susceptibility

to fluconazole and amphotericin B Diagn Microbiol Infect Dis 2002 4423ndash7

204 Levine J Bernard DB Idelson BA et al Fungal peritonitis compli-

cating continuous ambulatory peritoneal dialysis successful treatment

with fluconazole a new orally active antifungal agent Am J Med 1989

86 825ndash7

205 Michel C Courdavault L al Khayat R et al Fungal peritonitis in

patients on peritoneal dialysis Am J Nephrol 1994 14 113ndash20

206 WangAYYuAWLi PKet al Factors predicting outcomeof fungal

peritonitis in peritoneal dialysis analysis of a 9-year experience of fungal

peritonitis in a single center Am J Kidney Dis 2000 36 1183ndash92

207 Hawkins JL Baddour LM Candida lusitaniae infections in the era

of fluconazole availability Clin Infect Dis 2003 36 14ndash18

Review

409

208 KauffmanCAVazquezJASobel JDetal Prospectivemulticenter

surveillance study of funguria in hospitalized patients The National Insti-

tute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group

Clin Infect Dis 2000 30 14ndash18

209 Sobel JD Kauffman CA McKinsey D et al Candiduria a random-

ized double-blind study of treatment with fluconazole and placebo The

National Institute of Allergy and Infectious Diseases (NIAID) Mycoses

Study Group Clin Infect Dis 2000 30 19ndash24

210 LundstromTSobel JNosocomial candiduria a reviewClin Infect

Dis 2001 32 1602ndash7

211 Kaufman D Boyle R Hazen KC et al Fluconazole prophylaxis

against fungal colonization and infection in preterm infants N Engl J

Med 2001 345 1660ndash6

212 Kicklighter SD Springer SC Cox T et al Fluconazole for the pro-

phylaxis against candidal rectal colonization in the very low birth weight

infant Pediatrics 2001 107 293ndash8

213 McGuire W Clerihew L Austin N Prophylactic intravenous anti-

fungal agents to prevent mortality and morbidity in very low birth weight

infants Cochrane Database Syst Rev 2004 CD003850

214 Agarwal JBansalSMalikGKetal Trends inneonatal septicemia

emergence of non-albicans Candida Indian Pediatr 2004 41 712ndash15

215 FasanoCOrsquoKeefe JGibbsD Fluconazole treatment of neonates

and infants with severe fungal infections not treatable with conventional

agents Eur J Clin Microbiol Infect Dis 1994 13 351ndash4

216 Wainer S Cooper PA Gouws H et al Prospective study of flu-

conazole therapy in systemicneonatal fungal infectionPediatr InfectDis J

1997 16 763ndash7

217 Huang YC Lin TY Lien RI et al Fluconazole therapy in neonatal

candidemia Am J Perinatol 2000 17 411ndash15

218 Huttova M Hartmanova I Kralinsky K et al Candida fungemia in

neonates treated with fluconazole report of forty cases including eight

with meningitis Pediatr Infect Dis J 1998 17 1012ndash15

219 Gurpinar AN Balkan E Kilic N et al Fluconazole treatment of

neonates and infants with severe fungal infections J Int Med Res 1997

25 214ndash18

220 Driessen M Ellis JB Muwazi F et al The treatment of systemic

candidiasis in neonates with oral fluconazole Ann Trop Pediatr 1997 17263ndash71

221 Driessen M Ellis JB Cooper PA et al Fluconazole vs

amphotericin B for the treatment of neonatal fungal septicemia

a prospective randomized trial Pediatr Infect Dis J 1997 151107ndash12

222 Marr B Gross S Cunningham C et al Candidal sepsis and

meningitis in a very-low-birth-weight infant successfully treated with flu-

conazole and flucytosine Clin Infect Dis 1994 19 795ndash6

223 Oleinik EM Della-Latta P Rinaldi MG et al Candida lusitaniae

osteomyelitis in a premature infant Am J Perinatol 1993 10 313ndash15

224 Mondal RK Singhi SC Chakrabarti A Randomized comparison

between fluconazole and itraconazole for the treatment of candidemia in a

pediatric intensive care unit a preliminary study Pediatr Crit Care Med

2004 5 561ndash5

225 Viscoli C Castagnola E Fioredda F et al Fluconazole in the treat-

ment of candidiasis in immunocompromised children Antimicrob Agents

Chemother 1991 35 365ndash7

226 Decruyenaere J Colardyn F Vogelaers D et al Combined use of

fluconazole and selective digestive decontamination in the prevention of

fungal infection after adult liver transplantation Transplant Proc 1995 273515ndash16

227 Koh LP Kurup A Goh YT et al Randomized trial of fluconazole

versus low-dose amphotericin B in prophylaxis against fungal infections in

patients undergoing hematopoietic stem cell transplantationAmJHema-

tol 2002 71 260ndash7

228 Gluckman E Esperou-Bourdeau H Ribaud P et al Comparaison

entre le fluconazole et le ketoconazole pour la prophylaxie des infections

fongiques chez les patients traites par greffe de moelle allogenique Cah

Oncol 1993 2 167ndash9

Review

410

favoured by indwelling urinary catheters immunosuppressivedrugs or antibiotic prescriptions diabetes mellitus and extremeages C albicans is involved in half of the cases followed byC glabrata in 15 of the cases In 10 of cases infection involvesmore than one species208 Fluconazole achieves a 10 times higherconcentration in urine than in blood with powerful effect even onCglabrata infections Therefore it represents a first line treatment ofany Candida urinary tract infection

In a randomized placebo-controlled multicentre study amongpatients with asymptomatic candiduria Sobel et al209 found thatfluconazole (200 mgday) hastened the time to negative resultsof urine cultures However the rate of negative urine cultures2 weeks after the end of therapy was similar in the fluconazole-and placebo-treated groups showing the minimal utility of treat-ment in that setting Indeed asymptomatic candiduria should betreated only in high-risk situations namely patients with neutrope-nia infants with low birth weight patients with renal allografts andpatients who will undergo urologic manipulations (recommenda-tion of grade B-III from the IDSA) The optimal regimen in thatsetting is not known Short courses regimen are not recommendedand therapy for 1ndash2 weeks should be efficient

Ascending pyelonephritis treatment should also include ade-quate urinary drainage and removal of obstructive fungusballs210 Urinary tract devices should be optimally removed orat least replaced

Haematogenous renal involvement should be treated with high-dose parenteral fluconazole (6 mgkgday) in accordance with therecently published IDSA guidelines57

Fluconazole in childreninfants

No specific approval of fluconazole has been obtained inyoung children before the age of 6 months but a few studieshave evaluated its use in several settings

Prophylaxis of systemic candidiasis in neonates

Few studies have focused on the use of fluconazole as a prophy-lactic agent against invasive candidiasis in neonates Kaufmanet al211 demonstrated in 2001 the efficacy and safety of flucona-zole (3 mgkg every 3 days during the first 2 weeks then every2 days during the following 2 weeks and then every day until thesixth week of life) in extremely low birth weight and high-riskinfants (lt1000 g) in preventing both colonization and invasivefungal infection High risk was defined as the presence of a centralvascular catheter or endotracheal tube Indeed among the 50infants randomly assigned to fluconazole the rate of colonization(22) was significantly lower than in the 50 placebo-treated ones(60) no invasive fungal infection developed in the fluconazolegroup compared with a 20 rate of infection in the placebo groupNo adverse effect of fluconazole was documented

Kicklighter et al212 similarly observed the safety of fluconazoleat 6 mgkg (for 6 weeks) and its efficacy among neonates with lowbirth weight (lt1500 g) in the prevention of rectal colonization(however occurrence of invasive candidiasis was similar inboth groups) A Cochrane review of fluconazole prophylaxis inpreterm infants demonstrated a reduced risk of invasive infection(related risk 020) and mortality (related risk 044) in fluconazole-treated patients compared with placebo-treated patients213

Although concerns about resistance to azoles have been raised

the vast majority ofCandida spp strains have remained susceptibleto fluconazole over the past decade in this population40

Fluconazole in systemic candidiasis in childreninfants

Neonatal candidaemia Candidaemia is a major cause of sepsis inneonatal ICU representing up to 16 of all sepsis cases Therelated mortality rate is high often nearly 50214 Most casesare related to C albicans and C parapsilosis with a recent risein cases related to C tropicalis The main risk factors for invasivecandidiasis among neonates are low birth weight intravascularcatheters intratracheal intubation total parenteral nutrition andadministration of intralipid solution and recent administration ofbroad-spectrum antibiotics and corticosteroids10

Treatment with amphotericin B and 5-flucytosine has been thegold standard for years However amphotericin B has some seriousside effects which makes it mandatory to consider its use in thatsetting With good profile of tolerance good diffusion in all tissuesand body fluids and reliable oral absorption fluconazole has beenstudied as an alternative (see Table 15) In 1994 Fasano et al215

reported the compassionate use of fluconazole among 40 new-borns including 11 who presented with Candida sp meningitisThey were treated with a mean daily dosage of 5 mgkgday for amean duration of 26 days Of the 32 patients with evaluable out-come 31 experienced clearance of infection Other studies haveconfirmed these results in the recent years11216ndash220 In a multicen-tre prospective randomized study Driessen et al220 compared theefficacy and safety of either amphotericin B ndash 5-flucytosine orfluconazole (oral or intravenous dose of 10 mgkg as initialdose and then 5 mgkgday) in neonates with candidaemia Inthe fluconazole group 812 (67) survived versus 611 (55) inthe other group220 Among the four patients who died in the flu-conazole group two had treatment failure versus one in the ampho-tericin B group Cytolytic hepatitis was less frequent in thefluconazole-treated group Two isolated case reports also suggestthat the association of fluconazole and flucytosine might be syn-ergistic in the treatment of neonatal candidaemia222223

Very recently Mondal et al229 compared the efficacy and safetyof oral itraconazole versus oral fluconazole (both doses of 10 mgkgday) in newborns and paediatric patients with candidaemiaSimilar cure rate (81 and 82) mortality rate (95 and 135)and number of side effects were observed224 Fluconazole thusappears as a safe and effective systemic antifungal agent in thesetting of neonatal candidiasis

Children with systemic candidiasis Excluding the setting of neo-natal candidiasis very few studies have however focused on thepaediatric population when studying the efficiency of fluconazolefor the treatment of invasive candidiasis

In 1991 Viscoli et al reported the outcome of 24 immunocom-promised children treated with fluconazole (6 mgkgday) for 34episodes of proven invasive candidiasis A total of 3034 clinicaland microbiological cures were achieved Two patients with fun-gaemia due toC parapsilosis required an increase in dosage of up to12 mgkg Transient drug-related increases of liver transaminasesoccurred in two cases (6)225 In 1994 Fasano et al reported theoutcome of 63 children with AIDS cancer or transplantationprospectively receiving fluconazole as compassionate treatment(dose regimen ranging from 016 to 11 mgkgday mean 34 mgkgday)215 Half of them had fungaemia while the others hadrespiratory urinary tract or superficial oropharyngeal infections

Review

403

Clinical cure or improvement was achieved in 5263 (83) andpathogen eradication was achieved in 4359 (73)17 Huttovaet al218 reported in 1998 the outcome of 10 children withnosocomial fungal meningitis including 8 cases of candidal men-ingitis treated using fluconazole Five of them survived with clinicaland microbiological cure

Conclusions

Almost 15 years after its launch fluconazole remains a cornerstoneof antifungal prophylaxis and therapy of invasive candidiasis It hasan excellent pharmacokinetic and safety profile even in debilitatedpatients with good tissue penetration and a lack of major druginteractions particularly with immunosuppressive agents It can beprescribed in patients with renal failure if daily dosages are adaptedto the creatinine serum level Its spectrum of antimicrobial efficacyis reasonable and it remains active against most intrinsically sus-ceptible Candida spp encountered in systemic disease with lt5of C albicans resistant to fluconazole in that setting Although Ckrusei is intrinsically resistant to fluconazole it is rarely reported asa cause of systemic infection outside neutropenic patients Thus Cglabrata is the only species which might now limit the use offluconazole for the first line therapy of yeast fungaemia whenthe species is not identified Similarly patients who recentlyreceived fluconazole as antifungal prophylaxis should not be trea-ted with fluconazole for the curative treatment of a presumed orproven episode of systemic candidiasis The fungistatic effect offluconazole against Candida spp does not appear to influence theoutcome of candidaemic episodes at least in comparison withamphotericin B which is apparently fungicidal against Candidaspp Finally when summarizing its valuable properties the strongdemonstration of its efficacy in large randomized controlled trialsand selected clinical series its availability in various commercialpresentations and its current low cost fluconazole still remains aleading antifungal drug against susceptible Candida species

Transparency declarations

C C E H A L P R and F D have no conflicts to declareD W D In the past 5 years D W D has received grant supportfrom Astellas Merck Pfizer F2G OrthoBiotech Indevus Basileathe Fungal Research Trust the Wellcome Trust the National Insti-tute of Allergy and Infectious Diseases and the European Union Hehas been an advisorconsultant to Merck Basilea Vicuron (nowPfizer) Schering Plough Indevus F2G Nektar Daiichi SigmaTau Astellas PPL Therapeutics and Uriach He has been paid fortalks on behalf of Astellas Merck and Pfizer He holds foundershares in F2G Ltd and GBE Diagnostics Ltd and talks on behalf ofAstellas Merck and Gilead Sciences O L Speakers bureau forPfizer

References

1 Richardson K The discovery and profile of fluconazole J Chemo-

ther 1990 2 51ndash4

2 Richardson K Brammer KW Marriott MS et al Activity of

UK-49858 a bis-triazole derivative against experimental infections

with Candida albicans and Trichophyton mentagrophytes Antimicrob

Agents Chemother 1985 27 832ndash5

3 Vanrsquot Wout JW Mattie H van Furth R A prospective study of the

efficacyof fluconazole (UK-49858)againstdeep-seated fungal infections

J Antimicrob Chemother 1988 21 665ndash72Table

15

No

n-c

om

par

ativ

est

ud

ies

on

flu

con

azo

leas

cura

tiv

etr

eatm

ent

of

neo

nat

alca

nd

idae

mia

Ref

eren

ce

Nu

mb

ero

f

pat

ien

tsR

egim

enM

icro

bio

log

ical

cure

Sid

eef

fect

s

Dri

esse

net

al

22

02

1v

ery

low

bir

thw

eig

ht

5m

gk

gfo

r

1ndash

42

day

sm

ean

16

90

3

0

cyto

lyti

ch

epat

itis

Fas

anoet

al

21

54

05

mg

kg

for

2ndash

80

day

sm

ean

26

97

5

cy

toly

tic

hep

atit

is

Wai

ner

etal

21

61

91

0m

gk

go

nd

ay1

then

5m

gk

g

63

su

rviv

ing

32

fun

gal

free

dea

ths

NS

Hu

anget

al

21

71

8v

ery

low

bir

thw

eig

ht

3ndash

10

mg

kg

for

15

ndash1

73

day

sm

ean

34

6fi

rst

lin

etr

eatm

ent

83

13

afte

rA

MB

fail

ure

6

2

29

cy

toly

tic

hep

atit

is

Hu

tto

vaet

al

21

84

0v

ery

low

bir

thw

eig

ht

6m

gk

gfo

r6

ndash4

8d

ays

65

cu

rew

ith

ou

tre

lap

se5

cy

toly

tic

hep

atit

is

5

-ele

vat

edse

rum

crea

tin

ine

Gu

rpin

aret

al

21

92

42

ndash1

6m

gk

gfo

r

5ndash

72

day

sm

ean

25

96

8

an

aem

iao

rcy

toly

tic

hep

atit

is

Sch

war

zeet

al

11

53

5ndash

6m

gk

gfo

r3

wee

ks

mea

n2

17

8

4

cyto

lyti

ch

epat

itis

AM

B

amphote

rici

nB

ver

ylo

wbir

thw

eight

lt1500

g

NS

st

atis

tica

lly

not

signif

ican

t

Review

404

4 Vanrsquot Wout JW deGraeff-Meeder ER Paul LC et al Treatment of

two cases of cryptococcal meningitis with fluconazole Scand J Infect Dis

1988 20 193ndash8

5 Tucker RM Williams PL Arathoon EG et al Pharmacokinetics of

fluconazole in cerebrospinal fluid and serum in human coccidioidal

meningitis Antimicrob Agents Chemother 1988 32 369ndash73

6 ByrneWRWajszczukCPCryptococcalmeningitis in theacquired

immunodeficiency syndrome (AIDS) successful treatment with flucona-

zole after failure of amphotericin B Ann Intern Med 1988 108 384ndash5

7 HughesCE BeggsWH Action of fluconazole (UK-49858) in rela-

tion to other systemic antifungal azoles J Antimicrob Chemother 1987

19 171ndash4

8 DebruyneDClinicalpharmacokineticsof fluconazole insuperficial

and systemic mycoses Clin Pharmacokinet 1997 33 52ndash77

9 Brammer KW Coates PE Pharmacokinetics of fluconazole in

pediatric patients Eur J Clin Microbiol Infect Dis 1994 13 325ndash9

10 Schwarze R Penk A Pittrow L Administration of fluconazole in

children below 1 year of age Mycoses 1999 42 3ndash16

11 Schwarze R Penk A Pittrow L Treatment of candidal infections

with fluconazole in neonates and infants Eur J Med Res 2000 5 203ndash8

12 Thaler FBernardBTodMet al Fluconazolepenetration in cereb-

ral parenchyma in humans at steady stateAntimicrob Agents Chemother

1995 5 1154ndash6

13 Bozzette SA Gordon RL Yen A et al Biliary concentrations of

fluconazole in a patient with candidal cholecystitis case reportClin Infect

Dis 1992 4 701ndash3

14 Debruyne D Ryckelynck JP Moulin M et al Pharmacokinetics of

fluconazole in patients undergoing continuous ambulatory peritoneal dial-

ysis Clin Pharmacokinet 1990 18 491ndash8

15 Tod M Lortholary O Padoin C et al Intravenous penetration of

fluconazole during endophthalmitis Clin Microbiol Infect 1997 3 143ndash4

16 Urbak SF Degn T Fluconazole in the management of fungal ocu-

lar infections Ophthalmologica 1994 3 147ndash56

17 Fasano C OrsquoKeefe J Gibbs D Fluconazole treatment of children

with severe fungal infections not treatable with conventional agentsEur J

Clin Microbiol Infect Dis 1994 13 344ndash7

18 Aleck KA Bartley DL Multiple malformation syndrome following

fluconazole use in pregnancy report of an additional patient Am J Med

Genet 1997 72 253ndash6

19 Buijk SL Gyssens IC Mouton JW et al Pharmacokinetics of

sequential intravenous and enteral fluconazole in critically ill surgical

patients with invasive mycoses and compromised gastro-intestinal func-

tion Intensive Care Med 2001 27 115ndash21

20 El-Yazigi AEllisMErnstPet al Pharmacokinetics of oral flucona-

zole when used for prophylaxis in bone marrow transplant recipients

Antimicrob Agents Chemother 1997 41 914ndash17

21 Finch CK Green CA Self TH Fluconazole-carbamazepine inter-

action South Med J 2002 95 1099ndash100

22 Tucker RM Denning DW Hanson RH et al Interaction of azoles

with rifampin phenytoin and carbamazepine in vitro and clinical obser-

vations Clin Infect Dis 1992 14 165ndash74

23 Stockley IH Stockleyrsquos Drug Interactions A Source Book of Inter-

actions Their Mechanisms Clinical Importance and Management 6th

edn London UK Pharmaceutical Press 2002

24 von Moltke LL Greenblatt DJ Duan SX et al Inhibition of terfena-

dine metabolism in vitro by azole antifungal agents and by selective sero-

tonin reuptake inhibitor antidepressants relation to pharmacokinetic

interactions in vivo J Clin Psychopharmacol 1996 16 104ndash12

25 BrockmeyerNH Tillmann I Mertins L et al Pharmacokinetic inter-

action of fluconazole and zidovudine in HIV-positive patients Eur J Med

Res 1997 2 377ndash83

26 van Burik JA LeisenringW Myerson D et al The effect of prophy-

lactic fluconazole on the clinical spectrum of fungal diseases in bone

marrow transplant recipients with special attention to hepatic candidiasis

An autopsy study of 355 patients Medicine 1998 77 246ndash54

27 Wingard JR Antifungal chemoprophylaxis after blood andmarrow

transplantation Clin Infect Dis 2002 34 1386ndash90

28 GarbinoJLewDPRomandJAetalPreventionofsevereCandida

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double-blind placebo-controlled trial in patients treatedbyselectivediges-

tive decontamination Intensive Care Med 2002 28 1708ndash17

29 Gearhart MO Worsening of liver function with fluconazole and

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30 Crerar-Gilbert A Boots R Fraenkel D et al Survival following ful-

minant hepatic failure from fluconazole induced hepatitis Anaesth Inten-

sive Care 1999 27 650ndash2

31 PappasPGKauffmanCAPerfect Jetal Alopeciaassociatedwith

fluconazole therapy Ann Intern Med 1995 123 354ndash7

32 Stevens DA Diaz M Negroni R et al Safety evaluation of chronic

fluconazole therapy Fluconazole Pan-American Study Group

Chemotherapy 1997 5 371ndash7

33 Anaissie EJ Kontoyiannis DP Huls C et al Safety plasma con-

centrations and efficacy of high-dose fluconazole in invasive mold infec-

tions J Infect Dis 1995 172 599ndash602

34 Gussenhoven MJ Haak A Peereboom-Wynia JD et al Stevens-

Johnson syndrome after fluconazole Lancet 1991 338 120

35 NovelliVHolzelHSafetyand tolerabilityof fluconazole inchildrenAntimicrob Agents Chemother 1999 43 1955ndash60

36 Koks CH Crommentuyn KM Hoetelmans RM et al Can

fluconazole concentrations in saliva be used for therapeutic drug mon-

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37 Louie A Drusano GL Banerjee P et al Pharmacodynamics of

fluconazole in amurinemodel of systemic candidiasisAntimicrob Agents

Chemother 1998 42 1105ndash9

38 PittrowLPenkAPlasmaand tissueconcentrationsof fluconazole

and their correlation to breakpoints Mycoses 1997 40 25ndash32

39 Rex JH Pfaller MA Galgiani JN et al Development of interpretive

breakpoints forantifungalsusceptibility testing conceptual frameworkand

analysis of in vitro-in vivo correlation data for fluconazole itraconazole

and Candida infections Subcommittee on Antifungal Susceptibility Test-

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Dis 1997 24 235ndash47

40 Pfaller MA Diekema DJ Twelve years of fluconazole in clinical

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ticipant Group Clin Microbiol Infect 2004 10 Suppl 1 11ndash23

41 Tortorano AM Rigoni AL Biraghi E et al The European Confed-

eration of Medical Mycology (ECMM) survey of candidaemia in Italy anti-

fungal susceptibility patterns of 261 non-albicans Candida isolates from

blood J Antimicrob Chemother 2003 52 679ndash82

42 Pfaller MAMesser SA Boyken L et al Geographic variation in the

susceptibilities of invasive isolates of Candida glabrata to seven systemi-

cally active antifungal agents a global assessment from the ARTEMIS

Antifungal Surveillance Program conducted in 2001 and 2002 J Clin

Microbiol 2004 42 3142ndash6

43 Paya CV Fungal infections in solid-organ transplantation Clin

Infect Dis 1993 16 677ndash88

44 Singh N Wagener MM Marino IR et al Trends in invasive fungal

infections in liver transplant recipients correlation with evolution in trans-

plantation practices Transplantation 2002 73 63ndash7

45 Fung JJ Fungal infection in liver transplantation Transplant InfectDis 2002 4 18ndash23

46 Winston DJ Pakrasi A Busuttil RW Prophylactic fluconazole in

liver transplant recipientsA randomized double-blind placebo-controlled

trial Ann Intern Med 1999 131 729ndash37

47 Gladdy RA Richardson SE Davies HD et al Candida infection in

pediatric liver transplant recipients Liver Transpl Surg 1999 5 16ndash24

Review

405

48 Castaldo P Stratta RJ Wood RP et al Clinical spectrum of fungal

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trum and risk factors for invasive candidiasis in liver transplant recipients

prospective multicenter case-controlled study Transplantation 2003

75 2023ndash9

50 GeorgeMJ Snydman DRWerner BG et al The independent role

of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic

liver transplant recipients Boston Center for Liver Transplantation

CMVIG-Study Group Cytogam MedImmune Inc Gaithersburg Mary-

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51 Dockrell DH Mendez JC Jones M et al Human herpesvirus 6

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52 Tollemar J Ericzon BG Barkholt L et al Risk factors for deep

Candida infections in liver transplant recipients Transplant Proc 1990

22 1826ndash7

53 Lumbreras C Cuervas-Mons V Jara P et al Randomized trial of

fluconazole versus nystatin for the prophylaxis of Candida infection

following liver transplantation J Infect Dis 1996 174 583ndash8

54 Winston DJ Busuttil RW Randomized controlled trial of oral itra-

conazole solution versus intravenousoral fluconazole for prevention of

fungal infections in liver transplant recipients Transplantation 2002

74 688ndash95

55 Tortorano AM Viviani MA PaganoA et al Candida colonization in

orthotopic liver tranplantation fuconazole versus oral amphoericin B

J Mycol Med 1995 5 21ndash4

56 Kung N Fisher N Gunson B et al Fluconazole prophylaxis for

high-risk liver transplant recipients Lancet 1995 345 1234ndash5

57 Pappas PG Rex JH Sobel JD et al Guidelines for treatment of

candidiasis Clin Infect Dis 2004 38 161ndash89

58 PayaCV Prevention of fungal infection in transplantation TransplInfect Dis 2002 4 S46ndash51

59 LortholaryO Dupont B Antifungal prophylaxis during neutropenia

and immunodeficiency Clin Microbiol Rev 1997 10 477ndash504

60 Benedetti E Gruessner AC Troppmann C et al Intra-abdominal

fungal infections after pancreatic transplantation incidence treatment

and outcome J Am Coll Surg 1996 183 307ndash16

61 LumbrerasC Fernandez I Velosa J et al Infectious complications

following pancreatic transplantation incidence microbiological and clini-

cal characteristics and outcome Clin Infect Dis 1995 20 514ndash20

62 Patterson JE Epidemiology of fungal infections in solid organ

transplant patients Transpl Infect Dis 1999 1 229ndash36

63 Kusne S Furukawa H Abu-Elmagd K et al Infectious complica-

tions after small bowel transplantation in adults an update Transplant

Proc 1996 28 2761ndash2

64 Paterson DL Ndirangu M Kwak EJ et al Opportunistic infections

in solid-organ transplant recipients pre-treated with alumetuzumab In

Abstracts of the Forty-Fourth Interscience Conference on Antimicrobial

Agents and Chemotherapy Washington DC 2004 Abstract K-1427 p

357 American Society for Microbiology Washington DC USA

65 Kramer MR Marshall SE Starnes VA et al Infectious complica-

tions in heart-lung transplantation Analysis of 200 episodes Arch Intern

Med 1993 153 2010ndash6

66 Goodrich JMReedECMori M et al Clinical features and analysis

of risk factors for invasive candidal infection after marrow transplantation

J Infect Dis 1991 164 731ndash40

67 Dykewicz CA Centers for Disease Control and Prevention (US)

Infectious Diseases Society of America American Society of Blood and

MarrowTransplantation Summary of the guidelines for preventing oppor-

tunistic infections among hematopoietic stem cell transplant recipients

Clin Infect Dis 2001 33 139ndash44

68 Sable CA Donowitz GR Infections in bone marrow transplant

recipients Clin Infect Dis 1994 18 273ndash81

69 Goodman JLWinston DJ Greenfield RA et al A controlled trial of

fluconazole to prevent fungal infections in patients undergoing bone mar-

row transplantation N Engl J Med 1992 326 845ndash51

70 Slavin MA Osborne B Adams R et al Efficacy and safety of flu-

conazole prophylaxis for fungal infectionsaftermarrow transplantationmdasha

prospective randomized double-blind study J Infect Dis 1995 1711545ndash52

71 Marr KA Seidel K SlavinMA et al Prolonged fluconazole prophy-

laxis is associated with persistent protection against candidiasis-related

death in allogeneic marrow transplant recipients long-term follow-up of a

randomized placebo-controlled trial Blood 2000 96 2055ndash61

72 AlangadenGChandrasekar PH BaileyE et al Antifungal prophy-

laxis with low-dose fluconazole during bone marrow transplantation The

Bone Marrow Transplantation Team Bone Marrow Transplant 1994 14919ndash24

73 Wolff SN Fay J Stevens D et al Fluconazole versus low-dose

amphotericin B for the prevention of fungal infections in patients under-

going bonemarrow transplantation a study of theNorthAmericanMarrow

Transplant Group Bone Marrow Transplant 2000 25 853ndash9

74 Annaloro C Oriana A Tagliaferri E et al Efficacy of different pro-

phylactic antifungal regimens in bone marrow transplantation Haemato-

logica 1995 80 512ndash17

75 Winston DJ Maziarz RT Chandrasekar PH et al Intravenous and

oral itraconazole versus intravenous and oral fluconazole for long-term

antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant

recipients A multicenter randomized trial Ann Intern Med 2003 138705ndash13

76 MarrKACrippaF LeisenringWet al Itraconazoleversus flucona-

zole forpreventionof fungal infections inpatients receivingallogeneicstem

cell transplants Blood 2004 103 1527ndash33

77 MacMillan ML Goodman JL DeFor TE et al Fluconazole to pre-

vent yeast infections in bone marrow transplantation patients a random-

ized trial of high versus reduced dose and determination of the value of

maintenance therapy Am J Med 2002 112 369ndash79

78 Marr KA Seidel K White TC et al Candidemia in allogeneic blood

and marrow transplant recipients evolution of risk factors after the adop-

tion of prophylactic fluconazole J Infect Dis 2000 181 309ndash16

79 van Burik JA Ratanatharathorn V Stepan DE et al Micafungin

versus fluconazole for prophylaxis against invasive fungal infections dur-

ing neutropenia in patients undergoing hematopoietic stem cell trans-

plantation Clin Infect Dis 2004 39 1407ndash16

80 Prentice HG Kibbler CC Prentice AG Towards a targeted risk-

based antifungal strategy in neutropenic patients Br J Haematol 2000

110 273ndash84

81 Laverdiere M Rotstein C Bow EJ et al Impact of fluconazole

prophylaxis on fungal colonizatin and infection rates in neutropenic

patients The Canadian Fluconazole Study J Animicrob Chemother

2000 46 1001ndash8

82 Winston DJ Chandrasekar PH Lazarus HM et al Fluconazole

prophylaxis of fungal infections in patients with acute leukemia Results

of a randomized placebo-controlled double-blind multicenter trial Ann

Intern Med 1993 118 495ndash503

83 Chandrasekar PHGatnyCMEffect of fluconazole prophylaxis on

fever and use of amphotericin in neutropenic cancer patients Bone Mar-

row Transplantation Team Chemotherapy 1994 40 136ndash43

84 Rotstein C Bow EJ Laverdiere M et al Randomized placebo-

controlled trial of fluconazole prophylaxis for neutropenic cancer patients

benefit basedonpurposeand intensity of cytotoxic therapy TheCanadian

Fluconazole Prophylaxis Study Group Clin Infect Dis 1999 28 331ndash40

85 YamacK Senol E HaznedarR Prophylactic use of fluconazole in

neutropenic cancer patients Postgrad Med J 1997 71 284ndash6

86 KernW BehreG Rudolf T et al Failure of fluconazole prophylaxis

to reducemortality or the requirement of systemic amphotericin B therapy

during treatment for refractory acute myeloid leukemia results of a

Review

406

prospective randomized phase III study German AML Cooperative

Group Cancer 1998 83 291ndash301

87 SchaffnerA SchaffnerM Effect of prophylactic fluconazole on the

frequencyof fungal infectionsamphotericinBuseandhealthcarecosts in

patients undergoing intensive chemotherapy for hematologic neoplasias

J Infect Dis 1995 172 1035ndash41

88 Egger T Gratwohl A Tichelli A et al Comparison of fluconazole

with oral polyenes in the prevention of fungal infections in neutropenic

patients A prospective randomized single-center study Support Care

Cancer 1995 3 139ndash46

89 Morgenstern GR Prentice AG Prentice H et al A randomized

controlled trial of itraconazole versus fluconazole for the prevention of

fungal infections in patients with haematological malignancies UK Mul-

ticentre Antifungal Prophylaxis Study Group Br J Haematol 1999 105901ndash11

90 EllisMEClinkHErnstPetalControlledstudyof fluconazole in the

preventionof fungal infections in neutropenic patientswith haematological

malignancies and bone marrow transplant recipients Eur J Clin Microbiol

Infect Dis 1994 13 3ndash11

91 Philpott-Howard JN Wade JJ Mufti GJ et al Randomized com-

parisonoforal fluconazoleversusoralpolyenes for thepreventionof fungal

infection in patients at risk of neutropenia Multicentre Study Group

J Antimicrob Chemother 1993 31 973ndash84

92 Ninane J A multicentre study of fluconazole versus oral polyenes

in the prevention of fungal infection in children with hematological or

oncological malignancies Multicentre Study Group Eur J Clin Microbiol

Infect Dis 1994 13 330ndash7

93 Menichetti F Del Favero A Martino P et al Preventing fungal

infection in neutropenic patients with acute leukemia fluconazole com-

pared with oral amphotericin B The GIMEMA Infection Program Ann

Intern Med 1994 120 913ndash18

94 Akiyama H Mori S Tanikawa S et al Fluconazole versus oral

amphotericin B in preventing fungal infection in chemotherapy-induced

neutropenic patients with haematological malignancies Mycoses 1996

36 373ndash8

95 Meunier F AounM JanssensM et al Chemoprophylaxis of fungal

infections in granulocytopenic patients using fluconazole versus oral

amphotericin B Drug Invest 1991 3 258ndash65

96 Rozenberg-Arska M Dekker AW Branger J et al A randomized

study to compare oral fluconazole to amphotericin B in the prevention of

fungal infections inpatientswithacute leukaemiaJAntimicrobChemother

1991 27 369ndash76

97 Brammer KW Management of fungal infection in neutropenic

patients with fluconazole Haematol Blood Transfus 1990 33 546ndash50

98 Bodey GP Anaissie EJ Elting LS et al Antifungal prophylaxis

during remission induction therapy for acute leukemia fluconazole versus

intravenous amphotericin B Cancer 1994 73 2099ndash106

99 Kanda Y Yamamoto R Chizuka A et al Prophylactic action of

oral fluconazole against fungal infection in neutropenic patients A

meta-analysis of 16 randomized controlled trials Cancer 2000 891611ndash25

100 Bow EJ Laverdiere M Lussier N et al Antifungal prophylaxis for

severely neutropenic chemotherapy recipients a meta analysis of

randomized-controlled clinical trials Cancer 2002 94 3230ndash46

101 Viscoli C Paesmans M Sanz M et al Association between

antifungal prophylaxis and rate of documented bacteremia in febrile

neutropenic cancer patients Clin Infect Dis 2001 32 1532ndash7

102 HughesWT Armstrong D BodeyGP et al 2002 guidelines for the

use of antimicrobial agents in neutropenic patients with cancerClin Infect

Dis 2002 34 730ndash51

103 Cornely OA Bohme A Buchheidt D et al Prophylaxis of invasive

fungal infections in patients with hematological malignancies and solid

tumorsmdashguidelines of the Infectious Diseases Working Party (AGIHO)

of the German Society of Hematology and Oncology (DGHO) Ann

Hematol 2003 82 Suppl 2 186ndash200

104 McNeil MM Nash SL Hajjeh RA et al Trends in mortality due to

invasivemycotic diseases in theUnitedStates 1980ndash1997Clin InfectDis

2001 33 641ndash7

105 KibblerCCSeatonSBarnesRA et alManagement and outcome

of bloodstream infections due to Candida species in England and Wales

J Hosp Infect 2003 54 18ndash24

106 Marchetti O Bille J Fluckiger U et al Fungal Infection Network of

Switzerland Epidemiology of candidemia in Swiss tertiary care hospitals

secular trends 1991-2000 Clin Infect Dis 2004 38 311ndash20

107 Gudlaugsson O Gillespie S Lee K et al Attributable mortality of

nosocomial candidemia revisited Clin Infect Dis 2003 37 1172ndash7

108 Ibanez-Nolla J Nolla-Salas M Leon MA et al Early diagnosis of

candidiasis in nonneutropenic critically ill patients J Infect 2004 48181ndash92

109 BlumbergHMJarvisWRSoucieJMetalRisk factors for candidal

bloodstream infections in surgical intensive care unit patients the NEMIS

prospective multicenter study The National Epidemiology of Mycosis

Survey Clin Infect Dis 2001 33 177ndash86

110 Pittet D Monod M Suter PM et al Candida colonization and

subsequent infections in critically ill surgical patients Ann Surg 1994

220 751ndash8

111 Sendid B Poirot JL Tabouret M et al Combined detection of

mannanaemia and antimannan antibodies as a strategy for the diagnosis

of systemic infectioncausedbypathogenicCandidaspeciesJMedMicro-

biol 2002 51 433ndash42

112 Bar W Hecker H Diagnosis of systemic Candida infections in

patients of the intensive care unit Significance of serum antigens and

antibodies Mycoses 2002 45 22ndash8

113 Calandra T Marchetti O Clinical trials of antifungal prophy-

laxis among patients undergoing surgery Clin Infect Dis 2004 39S185ndash92

114 Sypula WT Kale-Pradhan PB Therapeutic dilemma of flucona-

zole prophylaxis in intensive care Ann Pharmacother 2002 36 155ndash9

115 Pelz RK Hendrix CW Swoboda SM et al Double-blind placebo-

controlled trial of fluconazole to prevent candidal infections in critically ill

surgical patients Ann Surg 2001 233 542ndash8

116 Eggimann P Francioli P Bille J et al Fluconazole prophylaxis

prevents intraabdominal candidiasis in high-risk surgical patients Crit

Care Med 1997 27 1066ndash72

117 Swoboda SM Merz WG Lipsetta PA Candidemia the impact of

antifungal prophylaxis in a surgical intensive care unitSurg Infect20034345ndash54

118 Todd JC OrsquoNeal VG Grady KP et al Reduction of secondary

mycotic infections in the trauma intensivie care unit with fluconazole

J Trauma 1991 31 1722ndash27

119 Jacobs S Price Evans DA Tariq M et al Fluconazole improves

survival in septic shock a randomized double-blind prospective studyCrit

Care Med 2003 31 1938ndash46

120 Zervos EE Fink GW Norman JG et al Fluconazole increases

bactericidal activity of neutrophils through non-cytokine-mediated path-

way J Trauma 1996 41 465ndash70

121 AblesAZBlumerNAValainisGTetal Fluconazoleprophylaxis of

severe Candida infection in trauma and postsurgical patients a prospec-

tive double-blind randomised placebo-controlled trial Infect Dis Clin

Pract 2000 9 169ndash75

122 Kam LW Lin JD Management of systemic candidal infections in

the intensive care unit Am J Health Syst Pharm 2002 59 33ndash41

123 Rocco TR Reinert SE Simms HH Effects of fluconazole admin-

istration in critically ill patients analysis of bacterial and fungal resistance

Arch Surg 2000 135 160ndash5

124 Tortorano AM Caspani L Rigoni AL et al Candidosis in the inten-

sive care unit a 20-year survey J Hosp Infect 2004 57 8ndash13

125 EggimannPGarbino J Pittet DManagement ofCandida species

infections in critically ill patients Lancet Infect Dis 2003 3 772ndash85

Review

407

126 EggimannPGarbinoJPittetDEpidemiologyofCandida species

infections incritically ill non-immunosuppressedpatientsLancet InfectDis

2003 3 685ndash702

127 Martins MD Lozano-Chiu M Rex JH Declining rates of oropha-

ryngeal candidiasis and carriage of Candida albicans associated with

trends toward reduced rates of carriage of fluconazole-resistant C albi-

cans in human immunodeficiency virus-infected patients Clin Infect Dis

1998 27 1291ndash4

128 Powderly WG Finkelstein D Feinberg J et al A randomized trial

comparing fluconazole with clotrimazole troches for the prevention of fun-

gal infections in patients with advanced human immunodeficiency virus

infection NIAID AIDS Clinical Trials Group N Engl J Med 1995 332700ndash5

129 Leen CL Dunbar EM Ellis ME et al Once-weekly fluconazole to

prevent recurrenceof oropharyngeal candidiasis inpatientswithAIDSand

AIDS-related complex a double-blind placebo-controlled study J Infect

1990 21 55ndash60

130 Stevens DA Greene SI Lang OS Thrush can be prevented in

patients with acquired immunodeficiency syndrome and the acquired

immunodeficiency syndrome-related complex Randomized double-

blind placebo-controlled study of 100-mg oral fluconazole daily Arch

Intern Med 1991 151 2458ndash64

131 Just-Nubling G Gentschew G Meissner K Fluconazole prophy-

laxis of recurrent oral candidiasis inHIV-positive patientsEur JClinMicro-

biol Infect Dis 1991 10 917ndash21

132 Marriott DJ Jones PD Hoy JF et al Fluconazole once a week as

secondary prophylaxis against oropharyngeal candidiasis in HIV-infected

patients A double-blind placebo-controlled studyMed J Aust 1993 158312ndash16

133 Schuman P Capps L Peng G et al Weekly fluconazole for the

prevention ofmucosal candidiasis inwomenwithHIV infection A random-

ized double-blind placebo-controlled trial Terry Beirn Community Pro-

grams for Clinical Research on AIDSAnn InternMed 1997 126 689ndash96

134 Havlir DV DubeMPMcCutchan JA et al Prophylaxis with weekly

versus daily fluconazole for fungal infections in patients with AIDS Clin

Infect Dis 1998 27 1369ndash75

135 Pagani JL Chave JP Casjka C et al Efficacy tolerability and

development of resistance in HIV-positive patients treated with flucona-

zole for secondary prevention of oropharyngeal candidiasis a random-

ized double-blind placebo-controlled trial JAntimicrobChemother 2002

50 231ndash40

136 Vazquez JA Peng G Sobel JD et al Evolution of antifungal sus-

ceptibility amongCandidaspecies isolates recovered fromhuman immun-

odeficiency virus-infected women receiving fluconazole prophylaxis Clin

Infect Dis 2001 33 1069ndash75

137 Delfraissy JF Prise en charge therapeutique des patients infectespas le VIH Rapport Delfraissy Paris Flammarion 2004

138 DePauwBERaemaekers JMDonnelly JPet al Anopenstudyon

the safety and efficacy of fluconazole in the treatment of disseminated

Candida infections in patients treated for hematological malignancy Ann

Hematol 1995 70 83ndash7

139 Anaissie EJ Vartivarian SE Abi-Said D et al Fluconazole versus

amphotericin B in the treatment of hematogenous candidiasis a matched

cohort study Am J Med 1996 101 170ndash6

140 Anaissie EJ Darouiche RO Abi-Said D et al Management of

invasive candidal infections results of a prospective randomized multi-

center study of fluconazole versus amphotericin B and review of the

literature Clin Infect Dis 1996 23 964ndash72

141 Myoken Y Kyo T Kohara T et al Breakthrough fungemia caused

by azole-resistant Candida albicans in neutropenic patients with acute

leukemia Clin Infect Dis 2003 36 1496ndash7

142 Anttila VJ FarkkilaM JanssonSE et al Diagnostic laparoscopy in

patientswith acute leukemiaandsuspectedhepatic candidiasisEur JClin

Microbiol Infect Dis 1997 16 637ndash43

143 Anaissie E Bodey GP Kantarjian H et al Fluconazole therapy for

chronic disseminated candidiasis in patients with leukemia and prior

amphotericin B therapy Am J Med 1991 91 142ndash50

144 KauffmanCA BradleySFRossSC et al Hepatosplenic candidia-

sis successful treatment with fluconazole Am J Med 1991 91 137ndash41

145 Kontoyiannis DP Luna MA Samuels BI et al Hepatosplenic can-

didiasis A manifestation of chronic disseminated candidiasis Infect Dis

Clin North Am 2000 14 721ndash39

146 Graninger W Presteril E Schneeweiss B et al Treatment of

Candida albicans fungaemia with fluconazole J Infect 1993 26 133ndash46

147 Phillips P Shafran S Garber G et al Multicenter randomized trial

of fluconazole versus amphotericin B for treatment of candidemia in

non-neutropenic patients Canadian Candidemia Study Group Eur J

Clin Microbiol Infect Dis 1997 16 337ndash45

148 Rex JH Bennett JE Sugar AM et alA randomized trial comparing

fluconazolewithamphotericinB for the treatmentof candidemia inpatients

without neutropenia Candidemia Study Group and the National Institute

N Engl J Med 1994 331 1325ndash30

149 Abele-Horn M Kopp A Sternberg U et al A randomized study

comparing fluconazolewith amphotericinB5-flucytosine for the treatment

of systemic Candida infections in intensive care patients Infection 1996

24 426ndash32

150 Nguyen MH Peacock JE Jr Tanner DC et al Therapeutic

approaches in patients with candidemia Evaluation in a multicenter

prospective observational study Arch Intern Med 1995 155 2429ndash35

151 Rex JH Pappas PG Karchmer AW et al A randomized and

blinded multicenter trial of high-dose fluconazole plus placebo versus flu-

conazole plus amphotericin B as therapy for candidemia and its con-

sequences in non-neutropenic subjectsClin Infect Dis 2003 36 1221ndash8

152 Mora-Duarte J Betts R Rotstein C et al Comparison of

caspofungin and amphotericin B for invasive candidiasis N Engl J Med

2002 347 2020ndash9

153 Sugar AM Saunders C Diamond RD et al Successful treatment

of Candida osteomyelitis with fluconazole A noncomparative study of

two patients Diagn Microbiol Infect Dis 1990 13 517ndash20

154 Tang C Successful treatment of Candida albicans osteomyelitis

with fluconazole J Infect 1993 26 89ndash92

155 LafontAOliveAGelmanMet alCandidaalbicansspondylodisci-

tis and vertebral osteomyelitis in patients with intravenous heroin drug

addiction Report of 3 new cases J Rheumatol 1994 21 953ndash6

156 Hennequin C Bouree P Hiesse C et al Spondylodiskitis due to

Candida albicans report of two patients who were successfully treated

with fluconazole and review of the literature Clin Infect Dis 1996 23176ndash8

157 Jonnalagadda S VeerabaguMP Rakela J et alCandida albicans

osteomyelitis in a liver transplant recipient a case report and review of the

literature Transplantation 1996 62 1182ndash4

158 Rossel P Schonheyder HC Nielsen H Fluconazole therapy

inCandidaalbicansspondylodiscitisScandJ InfectDis199830 527ndash30

159 TurnerDLJohnsonSARuleSASuccessful treatmentof candidal

osteomyelitis with fluconazole following failure with liposomal ampho-

tericin B J Infect 1999 38 51ndash3

160 El-Zaatari MM Hulten K Fares Y et al Successful treatment of

Candida albicans osteomyelitis of the spine with fluconazole and surgical

debridement case report J Chemother 2002 14 627ndash30

161 Seravalli L Van Linthoudt D Bernet C et al Candida glabrata

spinal osteomyelitis involving two contiguous lumbar vertebrae a case

report and review of the literature Diagn Microbiol Infect Dis 2003 45137ndash41

162 Garbino J Schnyder I LewDP et al An unusual cause of vertebral

osteomyelitis Candida species Scand J Infect Dis 2003 35 288ndash91

163 TunkelARThomasCYWispelweyBCandidaprostheticarthritis

report of a case treated with fluconazole and review of the literature Am J

Med 1993 94 100ndash3

Review

408

164 CushingRD FulgenziWR Synovial fluid levels of fluconazole in a

patient with Candida parapsilosis prosthetic joint infection who had an

excellent clinical response J Arthroplasty 1997 12 950

165 Fukasawa N Shirakura K Candida arthritis after total knee

arthroplastymdasha case of successful treatment without prosthesis removal

Acta Orthop Scand 1997 68 306ndash7

166 Lerch K Kalteis T Schubert T et al Prosthetic joint infections with

osteomyelitis due to Candida albicans Mycoses 2003 46 462ndash6

167 Clancy CJ Nguyen MH Morris AJ Candidal mediastinitis an

emerging clinical entity Clin Infect Dis 1997 25 608ndash13

168 PetrikkosGSkiadaA SabatakouH et al Case report Successful

treatment of two cases of post-surgical sternal osteomyelitis due to

Candida krusei and Candida albicans respectively with high doses of

triazoles (fluconazole itraconazole) Mycoses 2001 44 422ndash5

169 Weers-Pothoff GHavermans JF Kamphuis J et alCandida tropi-

calis arthritis in a patient with acutemyeloid leukemia successfully treated

with fluconazole case report and review of the literature Infection 1997

25 109ndash11

170 Laatikainen L TuominenM vonDickhoff K Treatment of endoge-

nous fungal endophthalmitis with systemic fluconazole with or without

vitrectomy Am J Ophthalmol 1992 113 205ndash7

171 Borne MJ Elliott JH OrsquoDay DM Ocular fluconazole treatment of

Candidaparapsilosisendophthalmitis after failed intravitreal amphotericin

B Arch Ophthalmol 1993 111 1326ndash7

172 Zarbin MA Becker E Witcher J et al Treatment of presumed

fungal endophthalmitis with oral fluconazole Ophthalmic Surg Lasers

1996 27 628ndash31

173 WongVK TasmanWEagleRC et al BilateralCandida parapsilo-

sis endophthalmitis Arch Ophthalmol 1997 115 670ndash2

174 Kauffman CA Bradley SF Vine AK Candida endophthalmitis

associated with intraocular lens implantation efficacy of fluconazole ther-

apy Mycoses 1993 36 13ndash17

175 del Palacio A Cuetara MS Ferro M et al Fluconazole in the man-

agement of endophthalmitis in disseminated candidosis of heroin addicts

Mycoses 1993 36 193ndash9

176 Luttrull JK Wan WL Kubak BM et al Treatment of ocular fungal

infections with oral fluconazole Am J Ophthalmol 1995 119 477ndash81

177 Akler ME Vellend H McNeely DM et al Use of fluconazole in the

treatment of candidal endophthalmitis Clin Infect Dis 1995 20 657ndash64

178 Christmas NJ Smiddy WE Vitrectomy and systemic fluconazole

for treatment of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1996 27 1012ndash18

179 EssmanTFFlynnHWSmiddyWEet al Treatment outcomes in a

10-year study of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1997 28 185ndash94

180 Martinez-Vazquez C Fernandez-Ulloa J Bordon J et al Candida

albicans endophthalmitis in brown heroin addicts response to early vit-

rectomyprecededand followedbyantifungal therapyClin InfectDis1998

27 1130ndash3

181 Aleixo MJ Caldeira L Ferreira ML Candida albicans meningitis

clinical case J Infect 2000 40 191ndash2

182 InoueY YozuR Ueda T et al A case report ofCandida parapsilo-

sis endocarditis J Heart Valve Dis 1998 7 240ndash2

183 Isalska BJ Stanbridge TN Fluconazole in the treatment of candi-

dal prosthetic valve endocarditis BMJ 1988 297 178ndash9

184 Martino P Meloni G Cassone A Candidal endocarditis and treat-

ment with fluconazole and granulocyte-macrophage colony-stimulating

factor Ann Intern Med 1990 112 966ndash7

185 Roupie E Darmon JY Brochard L et al Fluconazole therapy of

candidal native valveendocarditisEur JClinMicrobiol InfectDis199110458ndash9

186 Hernandez JA Gonzalez-Moreno M Llibre JM et al Candidal

mitral endocarditis and long-term treatment with fluconazole in a patient

with human immunodeficiency virus infection Clin Infect Dis 1992 151062ndash3

187 Venditti MDeBernardis FMicozzi A et al Fluconazole treatment

of catheter-related right-sided endocarditis caused by Candida albicans

and associated with endophthalmitis and folliculitis Clin Infect Dis 1992

14 422ndash6

188 Wallbridge DR McCartney AC Richardson MD Fluconazole in

the treatment ofCandidaprosthetic valveendocarditisMycoses199336259ndash61

189 Otaki M Kitamura N Candida prosthetic valve endocarditis An

autopsy review Int Surg 1993 78 252ndash3

190 Czwerwiec FS Bilsker MS Kamerman ML et al Long-term sur-

vival after fluconazole therapy of candidal prosthetic valve endocarditis

Am J Med 1993 94 545ndash6

191 Thakur RK Skelcy KM Kahn RN et al Successful treatment of

Candida prosthetic valve endocarditis with a combination of fluconazole

and amphotericin B Crit Care Med 1994 22 712ndash14

192 Cancelas JA Lopez JCabezudoE et al Native valve endocarditis

due toCandida parapsilosis a late complication after bonemarrow trans-

plantation-related fungemia Bone Marrow Transplant 1994 13 333ndash4

193 Zahid MA Klotz SA Hinthorn DR Medical treatment of recurrent

candidemia in a patient with probable Candida parapsilosis prosthetic

valve endocarditis Chest 1994 105 1597ndash8

194 Wells CJ Leech G Lever AM et al Treatment of native valve

Candida endocarditis with fluconazole J Infect 1995 31 233ndash5

195 Gilbert HM Peters ED Lang SJ et al Successful treatment of

fungal prosthetic valve endocarditis case report and review Clin Infect

Dis 1996 22 348ndash54

196 Nguyen MH Nguyen ML Yu VL et al Candida prosthetic valve

endocarditis prospective study of six cases and review of the literature

Clin Infect Dis 1996 22 262ndash7

197 Lejko-Zupanc T Kozelj M A case of recurrent Candida parapsilo-

sis prosthetic valve endocarditis cure bymedical treatment alone J Infect

1997 35 81ndash2

198 Joly V BelmatougN Leperre A et al Pacemaker endocarditis due

to Candida albicans case report and review Clin Infect Dis 1997 251359ndash62

199 Rex JH Walsh T Sobel JD et al Practice guidelines for the treat-

mentof candidiasis InfectiousDiseasesSocietyofAmericaClin InfectDis

2000 30 662ndash78

200 Baddour LM Long-term suppressive therapy for Candida para-

psilosis-induced prosthetic valve endocarditis Mayo Clin Proc 1995

70 773ndash5

201 Melgar GR Nasser RM Gordon SM Fungal prosthetic valve

endocarditis in 16 patients An 11-year experience in a tertiary care hos-

pital Medicine 1997 76 94ndash103

202 Dupont H Paugam-Burtz C Muller-Serieys C et al Predictive

factors of mortality due to polymicrobial peritonitis with Candida isolation

in peritoneal fluid in critically ill patients Arch Surg 2002 137 1341ndash6

203 Lee SC FungCP ChenHY et alCandida peritonitis due to peptic

ulcer perforation incidence rate risk factors prognosis and susceptibility

to fluconazole and amphotericin B Diagn Microbiol Infect Dis 2002 4423ndash7

204 Levine J Bernard DB Idelson BA et al Fungal peritonitis compli-

cating continuous ambulatory peritoneal dialysis successful treatment

with fluconazole a new orally active antifungal agent Am J Med 1989

86 825ndash7

205 Michel C Courdavault L al Khayat R et al Fungal peritonitis in

patients on peritoneal dialysis Am J Nephrol 1994 14 113ndash20

206 WangAYYuAWLi PKet al Factors predicting outcomeof fungal

peritonitis in peritoneal dialysis analysis of a 9-year experience of fungal

peritonitis in a single center Am J Kidney Dis 2000 36 1183ndash92

207 Hawkins JL Baddour LM Candida lusitaniae infections in the era

of fluconazole availability Clin Infect Dis 2003 36 14ndash18

Review

409

208 KauffmanCAVazquezJASobel JDetal Prospectivemulticenter

surveillance study of funguria in hospitalized patients The National Insti-

tute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group

Clin Infect Dis 2000 30 14ndash18

209 Sobel JD Kauffman CA McKinsey D et al Candiduria a random-

ized double-blind study of treatment with fluconazole and placebo The

National Institute of Allergy and Infectious Diseases (NIAID) Mycoses

Study Group Clin Infect Dis 2000 30 19ndash24

210 LundstromTSobel JNosocomial candiduria a reviewClin Infect

Dis 2001 32 1602ndash7

211 Kaufman D Boyle R Hazen KC et al Fluconazole prophylaxis

against fungal colonization and infection in preterm infants N Engl J

Med 2001 345 1660ndash6

212 Kicklighter SD Springer SC Cox T et al Fluconazole for the pro-

phylaxis against candidal rectal colonization in the very low birth weight

infant Pediatrics 2001 107 293ndash8

213 McGuire W Clerihew L Austin N Prophylactic intravenous anti-

fungal agents to prevent mortality and morbidity in very low birth weight

infants Cochrane Database Syst Rev 2004 CD003850

214 Agarwal JBansalSMalikGKetal Trends inneonatal septicemia

emergence of non-albicans Candida Indian Pediatr 2004 41 712ndash15

215 FasanoCOrsquoKeefe JGibbsD Fluconazole treatment of neonates

and infants with severe fungal infections not treatable with conventional

agents Eur J Clin Microbiol Infect Dis 1994 13 351ndash4

216 Wainer S Cooper PA Gouws H et al Prospective study of flu-

conazole therapy in systemicneonatal fungal infectionPediatr InfectDis J

1997 16 763ndash7

217 Huang YC Lin TY Lien RI et al Fluconazole therapy in neonatal

candidemia Am J Perinatol 2000 17 411ndash15

218 Huttova M Hartmanova I Kralinsky K et al Candida fungemia in

neonates treated with fluconazole report of forty cases including eight

with meningitis Pediatr Infect Dis J 1998 17 1012ndash15

219 Gurpinar AN Balkan E Kilic N et al Fluconazole treatment of

neonates and infants with severe fungal infections J Int Med Res 1997

25 214ndash18

220 Driessen M Ellis JB Muwazi F et al The treatment of systemic

candidiasis in neonates with oral fluconazole Ann Trop Pediatr 1997 17263ndash71

221 Driessen M Ellis JB Cooper PA et al Fluconazole vs

amphotericin B for the treatment of neonatal fungal septicemia

a prospective randomized trial Pediatr Infect Dis J 1997 151107ndash12

222 Marr B Gross S Cunningham C et al Candidal sepsis and

meningitis in a very-low-birth-weight infant successfully treated with flu-

conazole and flucytosine Clin Infect Dis 1994 19 795ndash6

223 Oleinik EM Della-Latta P Rinaldi MG et al Candida lusitaniae

osteomyelitis in a premature infant Am J Perinatol 1993 10 313ndash15

224 Mondal RK Singhi SC Chakrabarti A Randomized comparison

between fluconazole and itraconazole for the treatment of candidemia in a

pediatric intensive care unit a preliminary study Pediatr Crit Care Med

2004 5 561ndash5

225 Viscoli C Castagnola E Fioredda F et al Fluconazole in the treat-

ment of candidiasis in immunocompromised children Antimicrob Agents

Chemother 1991 35 365ndash7

226 Decruyenaere J Colardyn F Vogelaers D et al Combined use of

fluconazole and selective digestive decontamination in the prevention of

fungal infection after adult liver transplantation Transplant Proc 1995 273515ndash16

227 Koh LP Kurup A Goh YT et al Randomized trial of fluconazole

versus low-dose amphotericin B in prophylaxis against fungal infections in

patients undergoing hematopoietic stem cell transplantationAmJHema-

tol 2002 71 260ndash7

228 Gluckman E Esperou-Bourdeau H Ribaud P et al Comparaison

entre le fluconazole et le ketoconazole pour la prophylaxie des infections

fongiques chez les patients traites par greffe de moelle allogenique Cah

Oncol 1993 2 167ndash9

Review

410

Clinical cure or improvement was achieved in 5263 (83) andpathogen eradication was achieved in 4359 (73)17 Huttovaet al218 reported in 1998 the outcome of 10 children withnosocomial fungal meningitis including 8 cases of candidal men-ingitis treated using fluconazole Five of them survived with clinicaland microbiological cure

Conclusions

Almost 15 years after its launch fluconazole remains a cornerstoneof antifungal prophylaxis and therapy of invasive candidiasis It hasan excellent pharmacokinetic and safety profile even in debilitatedpatients with good tissue penetration and a lack of major druginteractions particularly with immunosuppressive agents It can beprescribed in patients with renal failure if daily dosages are adaptedto the creatinine serum level Its spectrum of antimicrobial efficacyis reasonable and it remains active against most intrinsically sus-ceptible Candida spp encountered in systemic disease with lt5of C albicans resistant to fluconazole in that setting Although Ckrusei is intrinsically resistant to fluconazole it is rarely reported asa cause of systemic infection outside neutropenic patients Thus Cglabrata is the only species which might now limit the use offluconazole for the first line therapy of yeast fungaemia whenthe species is not identified Similarly patients who recentlyreceived fluconazole as antifungal prophylaxis should not be trea-ted with fluconazole for the curative treatment of a presumed orproven episode of systemic candidiasis The fungistatic effect offluconazole against Candida spp does not appear to influence theoutcome of candidaemic episodes at least in comparison withamphotericin B which is apparently fungicidal against Candidaspp Finally when summarizing its valuable properties the strongdemonstration of its efficacy in large randomized controlled trialsand selected clinical series its availability in various commercialpresentations and its current low cost fluconazole still remains aleading antifungal drug against susceptible Candida species

Transparency declarations

C C E H A L P R and F D have no conflicts to declareD W D In the past 5 years D W D has received grant supportfrom Astellas Merck Pfizer F2G OrthoBiotech Indevus Basileathe Fungal Research Trust the Wellcome Trust the National Insti-tute of Allergy and Infectious Diseases and the European Union Hehas been an advisorconsultant to Merck Basilea Vicuron (nowPfizer) Schering Plough Indevus F2G Nektar Daiichi SigmaTau Astellas PPL Therapeutics and Uriach He has been paid fortalks on behalf of Astellas Merck and Pfizer He holds foundershares in F2G Ltd and GBE Diagnostics Ltd and talks on behalf ofAstellas Merck and Gilead Sciences O L Speakers bureau forPfizer

References

1 Richardson K The discovery and profile of fluconazole J Chemo-

ther 1990 2 51ndash4

2 Richardson K Brammer KW Marriott MS et al Activity of

UK-49858 a bis-triazole derivative against experimental infections

with Candida albicans and Trichophyton mentagrophytes Antimicrob

Agents Chemother 1985 27 832ndash5

3 Vanrsquot Wout JW Mattie H van Furth R A prospective study of the

efficacyof fluconazole (UK-49858)againstdeep-seated fungal infections

J Antimicrob Chemother 1988 21 665ndash72Table

15

No

n-c

om

par

ativ

est

ud

ies

on

flu

con

azo

leas

cura

tiv

etr

eatm

ent

of

neo

nat

alca

nd

idae

mia

Ref

eren

ce

Nu

mb

ero

f

pat

ien

tsR

egim

enM

icro

bio

log

ical

cure

Sid

eef

fect

s

Dri

esse

net

al

22

02

1v

ery

low

bir

thw

eig

ht

5m

gk

gfo

r

1ndash

42

day

sm

ean

16

90

3

0

cyto

lyti

ch

epat

itis

Fas

anoet

al

21

54

05

mg

kg

for

2ndash

80

day

sm

ean

26

97

5

cy

toly

tic

hep

atit

is

Wai

ner

etal

21

61

91

0m

gk

go

nd

ay1

then

5m

gk

g

63

su

rviv

ing

32

fun

gal

free

dea

ths

NS

Hu

anget

al

21

71

8v

ery

low

bir

thw

eig

ht

3ndash

10

mg

kg

for

15

ndash1

73

day

sm

ean

34

6fi

rst

lin

etr

eatm

ent

83

13

afte

rA

MB

fail

ure

6

2

29

cy

toly

tic

hep

atit

is

Hu

tto

vaet

al

21

84

0v

ery

low

bir

thw

eig

ht

6m

gk

gfo

r6

ndash4

8d

ays

65

cu

rew

ith

ou

tre

lap

se5

cy

toly

tic

hep

atit

is

5

-ele

vat

edse

rum

crea

tin

ine

Gu

rpin

aret

al

21

92

42

ndash1

6m

gk

gfo

r

5ndash

72

day

sm

ean

25

96

8

an

aem

iao

rcy

toly

tic

hep

atit

is

Sch

war

zeet

al

11

53

5ndash

6m

gk

gfo

r3

wee

ks

mea

n2

17

8

4

cyto

lyti

ch

epat

itis

AM

B

amphote

rici

nB

ver

ylo

wbir

thw

eight

lt1500

g

NS

st

atis

tica

lly

not

signif

ican

t

Review

404

4 Vanrsquot Wout JW deGraeff-Meeder ER Paul LC et al Treatment of

two cases of cryptococcal meningitis with fluconazole Scand J Infect Dis

1988 20 193ndash8

5 Tucker RM Williams PL Arathoon EG et al Pharmacokinetics of

fluconazole in cerebrospinal fluid and serum in human coccidioidal

meningitis Antimicrob Agents Chemother 1988 32 369ndash73

6 ByrneWRWajszczukCPCryptococcalmeningitis in theacquired

immunodeficiency syndrome (AIDS) successful treatment with flucona-

zole after failure of amphotericin B Ann Intern Med 1988 108 384ndash5

7 HughesCE BeggsWH Action of fluconazole (UK-49858) in rela-

tion to other systemic antifungal azoles J Antimicrob Chemother 1987

19 171ndash4

8 DebruyneDClinicalpharmacokineticsof fluconazole insuperficial

and systemic mycoses Clin Pharmacokinet 1997 33 52ndash77

9 Brammer KW Coates PE Pharmacokinetics of fluconazole in

pediatric patients Eur J Clin Microbiol Infect Dis 1994 13 325ndash9

10 Schwarze R Penk A Pittrow L Administration of fluconazole in

children below 1 year of age Mycoses 1999 42 3ndash16

11 Schwarze R Penk A Pittrow L Treatment of candidal infections

with fluconazole in neonates and infants Eur J Med Res 2000 5 203ndash8

12 Thaler FBernardBTodMet al Fluconazolepenetration in cereb-

ral parenchyma in humans at steady stateAntimicrob Agents Chemother

1995 5 1154ndash6

13 Bozzette SA Gordon RL Yen A et al Biliary concentrations of

fluconazole in a patient with candidal cholecystitis case reportClin Infect

Dis 1992 4 701ndash3

14 Debruyne D Ryckelynck JP Moulin M et al Pharmacokinetics of

fluconazole in patients undergoing continuous ambulatory peritoneal dial-

ysis Clin Pharmacokinet 1990 18 491ndash8

15 Tod M Lortholary O Padoin C et al Intravenous penetration of

fluconazole during endophthalmitis Clin Microbiol Infect 1997 3 143ndash4

16 Urbak SF Degn T Fluconazole in the management of fungal ocu-

lar infections Ophthalmologica 1994 3 147ndash56

17 Fasano C OrsquoKeefe J Gibbs D Fluconazole treatment of children

with severe fungal infections not treatable with conventional agentsEur J

Clin Microbiol Infect Dis 1994 13 344ndash7

18 Aleck KA Bartley DL Multiple malformation syndrome following

fluconazole use in pregnancy report of an additional patient Am J Med

Genet 1997 72 253ndash6

19 Buijk SL Gyssens IC Mouton JW et al Pharmacokinetics of

sequential intravenous and enteral fluconazole in critically ill surgical

patients with invasive mycoses and compromised gastro-intestinal func-

tion Intensive Care Med 2001 27 115ndash21

20 El-Yazigi AEllisMErnstPet al Pharmacokinetics of oral flucona-

zole when used for prophylaxis in bone marrow transplant recipients

Antimicrob Agents Chemother 1997 41 914ndash17

21 Finch CK Green CA Self TH Fluconazole-carbamazepine inter-

action South Med J 2002 95 1099ndash100

22 Tucker RM Denning DW Hanson RH et al Interaction of azoles

with rifampin phenytoin and carbamazepine in vitro and clinical obser-

vations Clin Infect Dis 1992 14 165ndash74

23 Stockley IH Stockleyrsquos Drug Interactions A Source Book of Inter-

actions Their Mechanisms Clinical Importance and Management 6th

edn London UK Pharmaceutical Press 2002

24 von Moltke LL Greenblatt DJ Duan SX et al Inhibition of terfena-

dine metabolism in vitro by azole antifungal agents and by selective sero-

tonin reuptake inhibitor antidepressants relation to pharmacokinetic

interactions in vivo J Clin Psychopharmacol 1996 16 104ndash12

25 BrockmeyerNH Tillmann I Mertins L et al Pharmacokinetic inter-

action of fluconazole and zidovudine in HIV-positive patients Eur J Med

Res 1997 2 377ndash83

26 van Burik JA LeisenringW Myerson D et al The effect of prophy-

lactic fluconazole on the clinical spectrum of fungal diseases in bone

marrow transplant recipients with special attention to hepatic candidiasis

An autopsy study of 355 patients Medicine 1998 77 246ndash54

27 Wingard JR Antifungal chemoprophylaxis after blood andmarrow

transplantation Clin Infect Dis 2002 34 1386ndash90

28 GarbinoJLewDPRomandJAetalPreventionofsevereCandida

infections in nonneutropenic high-risk critically ill patients a randomized

double-blind placebo-controlled trial in patients treatedbyselectivediges-

tive decontamination Intensive Care Med 2002 28 1708ndash17

29 Gearhart MO Worsening of liver function with fluconazole and

review of azole antifungal hepatotoxicity Ann Pharmacother 1994 281177ndash81

30 Crerar-Gilbert A Boots R Fraenkel D et al Survival following ful-

minant hepatic failure from fluconazole induced hepatitis Anaesth Inten-

sive Care 1999 27 650ndash2

31 PappasPGKauffmanCAPerfect Jetal Alopeciaassociatedwith

fluconazole therapy Ann Intern Med 1995 123 354ndash7

32 Stevens DA Diaz M Negroni R et al Safety evaluation of chronic

fluconazole therapy Fluconazole Pan-American Study Group

Chemotherapy 1997 5 371ndash7

33 Anaissie EJ Kontoyiannis DP Huls C et al Safety plasma con-

centrations and efficacy of high-dose fluconazole in invasive mold infec-

tions J Infect Dis 1995 172 599ndash602

34 Gussenhoven MJ Haak A Peereboom-Wynia JD et al Stevens-

Johnson syndrome after fluconazole Lancet 1991 338 120

35 NovelliVHolzelHSafetyand tolerabilityof fluconazole inchildrenAntimicrob Agents Chemother 1999 43 1955ndash60

36 Koks CH Crommentuyn KM Hoetelmans RM et al Can

fluconazole concentrations in saliva be used for therapeutic drug mon-

itoring Ther Drug Monit 2001 4 449ndash53

37 Louie A Drusano GL Banerjee P et al Pharmacodynamics of

fluconazole in amurinemodel of systemic candidiasisAntimicrob Agents

Chemother 1998 42 1105ndash9

38 PittrowLPenkAPlasmaand tissueconcentrationsof fluconazole

and their correlation to breakpoints Mycoses 1997 40 25ndash32

39 Rex JH Pfaller MA Galgiani JN et al Development of interpretive

breakpoints forantifungalsusceptibility testing conceptual frameworkand

analysis of in vitro-in vivo correlation data for fluconazole itraconazole

and Candida infections Subcommittee on Antifungal Susceptibility Test-

ingof theNationalCommittee forClinical LaboratoryStandardsClin Infect

Dis 1997 24 235ndash47

40 Pfaller MA Diekema DJ Twelve years of fluconazole in clinical

practiceglobal trends inspeciesdistributionand fluconazolesusceptibility

of bloodstream isolatesofCandida International FungalSurveillancePar-

ticipant Group Clin Microbiol Infect 2004 10 Suppl 1 11ndash23

41 Tortorano AM Rigoni AL Biraghi E et al The European Confed-

eration of Medical Mycology (ECMM) survey of candidaemia in Italy anti-

fungal susceptibility patterns of 261 non-albicans Candida isolates from

blood J Antimicrob Chemother 2003 52 679ndash82

42 Pfaller MAMesser SA Boyken L et al Geographic variation in the

susceptibilities of invasive isolates of Candida glabrata to seven systemi-

cally active antifungal agents a global assessment from the ARTEMIS

Antifungal Surveillance Program conducted in 2001 and 2002 J Clin

Microbiol 2004 42 3142ndash6

43 Paya CV Fungal infections in solid-organ transplantation Clin

Infect Dis 1993 16 677ndash88

44 Singh N Wagener MM Marino IR et al Trends in invasive fungal

infections in liver transplant recipients correlation with evolution in trans-

plantation practices Transplantation 2002 73 63ndash7

45 Fung JJ Fungal infection in liver transplantation Transplant InfectDis 2002 4 18ndash23

46 Winston DJ Pakrasi A Busuttil RW Prophylactic fluconazole in

liver transplant recipientsA randomized double-blind placebo-controlled

trial Ann Intern Med 1999 131 729ndash37

47 Gladdy RA Richardson SE Davies HD et al Candida infection in

pediatric liver transplant recipients Liver Transpl Surg 1999 5 16ndash24

Review

405

48 Castaldo P Stratta RJ Wood RP et al Clinical spectrum of fungal

infections after orthotopic liver transplantation Arch Surg 1991 126149ndash56

49 Husain S Tollemar J Dominguez EA et al Changes in the spec-

trum and risk factors for invasive candidiasis in liver transplant recipients

prospective multicenter case-controlled study Transplantation 2003

75 2023ndash9

50 GeorgeMJ Snydman DRWerner BG et al The independent role

of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic

liver transplant recipients Boston Center for Liver Transplantation

CMVIG-Study Group Cytogam MedImmune Inc Gaithersburg Mary-

land Am J Med 1997 103 106ndash13

51 Dockrell DH Mendez JC Jones M et al Human herpesvirus 6

seronegativity before transplantation predicts the occurrence of fungal

infection in liver transplant recipientsTransplantation 1999 67 399ndash403

52 Tollemar J Ericzon BG Barkholt L et al Risk factors for deep

Candida infections in liver transplant recipients Transplant Proc 1990

22 1826ndash7

53 Lumbreras C Cuervas-Mons V Jara P et al Randomized trial of

fluconazole versus nystatin for the prophylaxis of Candida infection

following liver transplantation J Infect Dis 1996 174 583ndash8

54 Winston DJ Busuttil RW Randomized controlled trial of oral itra-

conazole solution versus intravenousoral fluconazole for prevention of

fungal infections in liver transplant recipients Transplantation 2002

74 688ndash95

55 Tortorano AM Viviani MA PaganoA et al Candida colonization in

orthotopic liver tranplantation fuconazole versus oral amphoericin B

J Mycol Med 1995 5 21ndash4

56 Kung N Fisher N Gunson B et al Fluconazole prophylaxis for

high-risk liver transplant recipients Lancet 1995 345 1234ndash5

57 Pappas PG Rex JH Sobel JD et al Guidelines for treatment of

candidiasis Clin Infect Dis 2004 38 161ndash89

58 PayaCV Prevention of fungal infection in transplantation TransplInfect Dis 2002 4 S46ndash51

59 LortholaryO Dupont B Antifungal prophylaxis during neutropenia

and immunodeficiency Clin Microbiol Rev 1997 10 477ndash504

60 Benedetti E Gruessner AC Troppmann C et al Intra-abdominal

fungal infections after pancreatic transplantation incidence treatment

and outcome J Am Coll Surg 1996 183 307ndash16

61 LumbrerasC Fernandez I Velosa J et al Infectious complications

following pancreatic transplantation incidence microbiological and clini-

cal characteristics and outcome Clin Infect Dis 1995 20 514ndash20

62 Patterson JE Epidemiology of fungal infections in solid organ

transplant patients Transpl Infect Dis 1999 1 229ndash36

63 Kusne S Furukawa H Abu-Elmagd K et al Infectious complica-

tions after small bowel transplantation in adults an update Transplant

Proc 1996 28 2761ndash2

64 Paterson DL Ndirangu M Kwak EJ et al Opportunistic infections

in solid-organ transplant recipients pre-treated with alumetuzumab In

Abstracts of the Forty-Fourth Interscience Conference on Antimicrobial

Agents and Chemotherapy Washington DC 2004 Abstract K-1427 p

357 American Society for Microbiology Washington DC USA

65 Kramer MR Marshall SE Starnes VA et al Infectious complica-

tions in heart-lung transplantation Analysis of 200 episodes Arch Intern

Med 1993 153 2010ndash6

66 Goodrich JMReedECMori M et al Clinical features and analysis

of risk factors for invasive candidal infection after marrow transplantation

J Infect Dis 1991 164 731ndash40

67 Dykewicz CA Centers for Disease Control and Prevention (US)

Infectious Diseases Society of America American Society of Blood and

MarrowTransplantation Summary of the guidelines for preventing oppor-

tunistic infections among hematopoietic stem cell transplant recipients

Clin Infect Dis 2001 33 139ndash44

68 Sable CA Donowitz GR Infections in bone marrow transplant

recipients Clin Infect Dis 1994 18 273ndash81

69 Goodman JLWinston DJ Greenfield RA et al A controlled trial of

fluconazole to prevent fungal infections in patients undergoing bone mar-

row transplantation N Engl J Med 1992 326 845ndash51

70 Slavin MA Osborne B Adams R et al Efficacy and safety of flu-

conazole prophylaxis for fungal infectionsaftermarrow transplantationmdasha

prospective randomized double-blind study J Infect Dis 1995 1711545ndash52

71 Marr KA Seidel K SlavinMA et al Prolonged fluconazole prophy-

laxis is associated with persistent protection against candidiasis-related

death in allogeneic marrow transplant recipients long-term follow-up of a

randomized placebo-controlled trial Blood 2000 96 2055ndash61

72 AlangadenGChandrasekar PH BaileyE et al Antifungal prophy-

laxis with low-dose fluconazole during bone marrow transplantation The

Bone Marrow Transplantation Team Bone Marrow Transplant 1994 14919ndash24

73 Wolff SN Fay J Stevens D et al Fluconazole versus low-dose

amphotericin B for the prevention of fungal infections in patients under-

going bonemarrow transplantation a study of theNorthAmericanMarrow

Transplant Group Bone Marrow Transplant 2000 25 853ndash9

74 Annaloro C Oriana A Tagliaferri E et al Efficacy of different pro-

phylactic antifungal regimens in bone marrow transplantation Haemato-

logica 1995 80 512ndash17

75 Winston DJ Maziarz RT Chandrasekar PH et al Intravenous and

oral itraconazole versus intravenous and oral fluconazole for long-term

antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant

recipients A multicenter randomized trial Ann Intern Med 2003 138705ndash13

76 MarrKACrippaF LeisenringWet al Itraconazoleversus flucona-

zole forpreventionof fungal infections inpatients receivingallogeneicstem

cell transplants Blood 2004 103 1527ndash33

77 MacMillan ML Goodman JL DeFor TE et al Fluconazole to pre-

vent yeast infections in bone marrow transplantation patients a random-

ized trial of high versus reduced dose and determination of the value of

maintenance therapy Am J Med 2002 112 369ndash79

78 Marr KA Seidel K White TC et al Candidemia in allogeneic blood

and marrow transplant recipients evolution of risk factors after the adop-

tion of prophylactic fluconazole J Infect Dis 2000 181 309ndash16

79 van Burik JA Ratanatharathorn V Stepan DE et al Micafungin

versus fluconazole for prophylaxis against invasive fungal infections dur-

ing neutropenia in patients undergoing hematopoietic stem cell trans-

plantation Clin Infect Dis 2004 39 1407ndash16

80 Prentice HG Kibbler CC Prentice AG Towards a targeted risk-

based antifungal strategy in neutropenic patients Br J Haematol 2000

110 273ndash84

81 Laverdiere M Rotstein C Bow EJ et al Impact of fluconazole

prophylaxis on fungal colonizatin and infection rates in neutropenic

patients The Canadian Fluconazole Study J Animicrob Chemother

2000 46 1001ndash8

82 Winston DJ Chandrasekar PH Lazarus HM et al Fluconazole

prophylaxis of fungal infections in patients with acute leukemia Results

of a randomized placebo-controlled double-blind multicenter trial Ann

Intern Med 1993 118 495ndash503

83 Chandrasekar PHGatnyCMEffect of fluconazole prophylaxis on

fever and use of amphotericin in neutropenic cancer patients Bone Mar-

row Transplantation Team Chemotherapy 1994 40 136ndash43

84 Rotstein C Bow EJ Laverdiere M et al Randomized placebo-

controlled trial of fluconazole prophylaxis for neutropenic cancer patients

benefit basedonpurposeand intensity of cytotoxic therapy TheCanadian

Fluconazole Prophylaxis Study Group Clin Infect Dis 1999 28 331ndash40

85 YamacK Senol E HaznedarR Prophylactic use of fluconazole in

neutropenic cancer patients Postgrad Med J 1997 71 284ndash6

86 KernW BehreG Rudolf T et al Failure of fluconazole prophylaxis

to reducemortality or the requirement of systemic amphotericin B therapy

during treatment for refractory acute myeloid leukemia results of a

Review

406

prospective randomized phase III study German AML Cooperative

Group Cancer 1998 83 291ndash301

87 SchaffnerA SchaffnerM Effect of prophylactic fluconazole on the

frequencyof fungal infectionsamphotericinBuseandhealthcarecosts in

patients undergoing intensive chemotherapy for hematologic neoplasias

J Infect Dis 1995 172 1035ndash41

88 Egger T Gratwohl A Tichelli A et al Comparison of fluconazole

with oral polyenes in the prevention of fungal infections in neutropenic

patients A prospective randomized single-center study Support Care

Cancer 1995 3 139ndash46

89 Morgenstern GR Prentice AG Prentice H et al A randomized

controlled trial of itraconazole versus fluconazole for the prevention of

fungal infections in patients with haematological malignancies UK Mul-

ticentre Antifungal Prophylaxis Study Group Br J Haematol 1999 105901ndash11

90 EllisMEClinkHErnstPetalControlledstudyof fluconazole in the

preventionof fungal infections in neutropenic patientswith haematological

malignancies and bone marrow transplant recipients Eur J Clin Microbiol

Infect Dis 1994 13 3ndash11

91 Philpott-Howard JN Wade JJ Mufti GJ et al Randomized com-

parisonoforal fluconazoleversusoralpolyenes for thepreventionof fungal

infection in patients at risk of neutropenia Multicentre Study Group

J Antimicrob Chemother 1993 31 973ndash84

92 Ninane J A multicentre study of fluconazole versus oral polyenes

in the prevention of fungal infection in children with hematological or

oncological malignancies Multicentre Study Group Eur J Clin Microbiol

Infect Dis 1994 13 330ndash7

93 Menichetti F Del Favero A Martino P et al Preventing fungal

infection in neutropenic patients with acute leukemia fluconazole com-

pared with oral amphotericin B The GIMEMA Infection Program Ann

Intern Med 1994 120 913ndash18

94 Akiyama H Mori S Tanikawa S et al Fluconazole versus oral

amphotericin B in preventing fungal infection in chemotherapy-induced

neutropenic patients with haematological malignancies Mycoses 1996

36 373ndash8

95 Meunier F AounM JanssensM et al Chemoprophylaxis of fungal

infections in granulocytopenic patients using fluconazole versus oral

amphotericin B Drug Invest 1991 3 258ndash65

96 Rozenberg-Arska M Dekker AW Branger J et al A randomized

study to compare oral fluconazole to amphotericin B in the prevention of

fungal infections inpatientswithacute leukaemiaJAntimicrobChemother

1991 27 369ndash76

97 Brammer KW Management of fungal infection in neutropenic

patients with fluconazole Haematol Blood Transfus 1990 33 546ndash50

98 Bodey GP Anaissie EJ Elting LS et al Antifungal prophylaxis

during remission induction therapy for acute leukemia fluconazole versus

intravenous amphotericin B Cancer 1994 73 2099ndash106

99 Kanda Y Yamamoto R Chizuka A et al Prophylactic action of

oral fluconazole against fungal infection in neutropenic patients A

meta-analysis of 16 randomized controlled trials Cancer 2000 891611ndash25

100 Bow EJ Laverdiere M Lussier N et al Antifungal prophylaxis for

severely neutropenic chemotherapy recipients a meta analysis of

randomized-controlled clinical trials Cancer 2002 94 3230ndash46

101 Viscoli C Paesmans M Sanz M et al Association between

antifungal prophylaxis and rate of documented bacteremia in febrile

neutropenic cancer patients Clin Infect Dis 2001 32 1532ndash7

102 HughesWT Armstrong D BodeyGP et al 2002 guidelines for the

use of antimicrobial agents in neutropenic patients with cancerClin Infect

Dis 2002 34 730ndash51

103 Cornely OA Bohme A Buchheidt D et al Prophylaxis of invasive

fungal infections in patients with hematological malignancies and solid

tumorsmdashguidelines of the Infectious Diseases Working Party (AGIHO)

of the German Society of Hematology and Oncology (DGHO) Ann

Hematol 2003 82 Suppl 2 186ndash200

104 McNeil MM Nash SL Hajjeh RA et al Trends in mortality due to

invasivemycotic diseases in theUnitedStates 1980ndash1997Clin InfectDis

2001 33 641ndash7

105 KibblerCCSeatonSBarnesRA et alManagement and outcome

of bloodstream infections due to Candida species in England and Wales

J Hosp Infect 2003 54 18ndash24

106 Marchetti O Bille J Fluckiger U et al Fungal Infection Network of

Switzerland Epidemiology of candidemia in Swiss tertiary care hospitals

secular trends 1991-2000 Clin Infect Dis 2004 38 311ndash20

107 Gudlaugsson O Gillespie S Lee K et al Attributable mortality of

nosocomial candidemia revisited Clin Infect Dis 2003 37 1172ndash7

108 Ibanez-Nolla J Nolla-Salas M Leon MA et al Early diagnosis of

candidiasis in nonneutropenic critically ill patients J Infect 2004 48181ndash92

109 BlumbergHMJarvisWRSoucieJMetalRisk factors for candidal

bloodstream infections in surgical intensive care unit patients the NEMIS

prospective multicenter study The National Epidemiology of Mycosis

Survey Clin Infect Dis 2001 33 177ndash86

110 Pittet D Monod M Suter PM et al Candida colonization and

subsequent infections in critically ill surgical patients Ann Surg 1994

220 751ndash8

111 Sendid B Poirot JL Tabouret M et al Combined detection of

mannanaemia and antimannan antibodies as a strategy for the diagnosis

of systemic infectioncausedbypathogenicCandidaspeciesJMedMicro-

biol 2002 51 433ndash42

112 Bar W Hecker H Diagnosis of systemic Candida infections in

patients of the intensive care unit Significance of serum antigens and

antibodies Mycoses 2002 45 22ndash8

113 Calandra T Marchetti O Clinical trials of antifungal prophy-

laxis among patients undergoing surgery Clin Infect Dis 2004 39S185ndash92

114 Sypula WT Kale-Pradhan PB Therapeutic dilemma of flucona-

zole prophylaxis in intensive care Ann Pharmacother 2002 36 155ndash9

115 Pelz RK Hendrix CW Swoboda SM et al Double-blind placebo-

controlled trial of fluconazole to prevent candidal infections in critically ill

surgical patients Ann Surg 2001 233 542ndash8

116 Eggimann P Francioli P Bille J et al Fluconazole prophylaxis

prevents intraabdominal candidiasis in high-risk surgical patients Crit

Care Med 1997 27 1066ndash72

117 Swoboda SM Merz WG Lipsetta PA Candidemia the impact of

antifungal prophylaxis in a surgical intensive care unitSurg Infect20034345ndash54

118 Todd JC OrsquoNeal VG Grady KP et al Reduction of secondary

mycotic infections in the trauma intensivie care unit with fluconazole

J Trauma 1991 31 1722ndash27

119 Jacobs S Price Evans DA Tariq M et al Fluconazole improves

survival in septic shock a randomized double-blind prospective studyCrit

Care Med 2003 31 1938ndash46

120 Zervos EE Fink GW Norman JG et al Fluconazole increases

bactericidal activity of neutrophils through non-cytokine-mediated path-

way J Trauma 1996 41 465ndash70

121 AblesAZBlumerNAValainisGTetal Fluconazoleprophylaxis of

severe Candida infection in trauma and postsurgical patients a prospec-

tive double-blind randomised placebo-controlled trial Infect Dis Clin

Pract 2000 9 169ndash75

122 Kam LW Lin JD Management of systemic candidal infections in

the intensive care unit Am J Health Syst Pharm 2002 59 33ndash41

123 Rocco TR Reinert SE Simms HH Effects of fluconazole admin-

istration in critically ill patients analysis of bacterial and fungal resistance

Arch Surg 2000 135 160ndash5

124 Tortorano AM Caspani L Rigoni AL et al Candidosis in the inten-

sive care unit a 20-year survey J Hosp Infect 2004 57 8ndash13

125 EggimannPGarbino J Pittet DManagement ofCandida species

infections in critically ill patients Lancet Infect Dis 2003 3 772ndash85

Review

407

126 EggimannPGarbinoJPittetDEpidemiologyofCandida species

infections incritically ill non-immunosuppressedpatientsLancet InfectDis

2003 3 685ndash702

127 Martins MD Lozano-Chiu M Rex JH Declining rates of oropha-

ryngeal candidiasis and carriage of Candida albicans associated with

trends toward reduced rates of carriage of fluconazole-resistant C albi-

cans in human immunodeficiency virus-infected patients Clin Infect Dis

1998 27 1291ndash4

128 Powderly WG Finkelstein D Feinberg J et al A randomized trial

comparing fluconazole with clotrimazole troches for the prevention of fun-

gal infections in patients with advanced human immunodeficiency virus

infection NIAID AIDS Clinical Trials Group N Engl J Med 1995 332700ndash5

129 Leen CL Dunbar EM Ellis ME et al Once-weekly fluconazole to

prevent recurrenceof oropharyngeal candidiasis inpatientswithAIDSand

AIDS-related complex a double-blind placebo-controlled study J Infect

1990 21 55ndash60

130 Stevens DA Greene SI Lang OS Thrush can be prevented in

patients with acquired immunodeficiency syndrome and the acquired

immunodeficiency syndrome-related complex Randomized double-

blind placebo-controlled study of 100-mg oral fluconazole daily Arch

Intern Med 1991 151 2458ndash64

131 Just-Nubling G Gentschew G Meissner K Fluconazole prophy-

laxis of recurrent oral candidiasis inHIV-positive patientsEur JClinMicro-

biol Infect Dis 1991 10 917ndash21

132 Marriott DJ Jones PD Hoy JF et al Fluconazole once a week as

secondary prophylaxis against oropharyngeal candidiasis in HIV-infected

patients A double-blind placebo-controlled studyMed J Aust 1993 158312ndash16

133 Schuman P Capps L Peng G et al Weekly fluconazole for the

prevention ofmucosal candidiasis inwomenwithHIV infection A random-

ized double-blind placebo-controlled trial Terry Beirn Community Pro-

grams for Clinical Research on AIDSAnn InternMed 1997 126 689ndash96

134 Havlir DV DubeMPMcCutchan JA et al Prophylaxis with weekly

versus daily fluconazole for fungal infections in patients with AIDS Clin

Infect Dis 1998 27 1369ndash75

135 Pagani JL Chave JP Casjka C et al Efficacy tolerability and

development of resistance in HIV-positive patients treated with flucona-

zole for secondary prevention of oropharyngeal candidiasis a random-

ized double-blind placebo-controlled trial JAntimicrobChemother 2002

50 231ndash40

136 Vazquez JA Peng G Sobel JD et al Evolution of antifungal sus-

ceptibility amongCandidaspecies isolates recovered fromhuman immun-

odeficiency virus-infected women receiving fluconazole prophylaxis Clin

Infect Dis 2001 33 1069ndash75

137 Delfraissy JF Prise en charge therapeutique des patients infectespas le VIH Rapport Delfraissy Paris Flammarion 2004

138 DePauwBERaemaekers JMDonnelly JPet al Anopenstudyon

the safety and efficacy of fluconazole in the treatment of disseminated

Candida infections in patients treated for hematological malignancy Ann

Hematol 1995 70 83ndash7

139 Anaissie EJ Vartivarian SE Abi-Said D et al Fluconazole versus

amphotericin B in the treatment of hematogenous candidiasis a matched

cohort study Am J Med 1996 101 170ndash6

140 Anaissie EJ Darouiche RO Abi-Said D et al Management of

invasive candidal infections results of a prospective randomized multi-

center study of fluconazole versus amphotericin B and review of the

literature Clin Infect Dis 1996 23 964ndash72

141 Myoken Y Kyo T Kohara T et al Breakthrough fungemia caused

by azole-resistant Candida albicans in neutropenic patients with acute

leukemia Clin Infect Dis 2003 36 1496ndash7

142 Anttila VJ FarkkilaM JanssonSE et al Diagnostic laparoscopy in

patientswith acute leukemiaandsuspectedhepatic candidiasisEur JClin

Microbiol Infect Dis 1997 16 637ndash43

143 Anaissie E Bodey GP Kantarjian H et al Fluconazole therapy for

chronic disseminated candidiasis in patients with leukemia and prior

amphotericin B therapy Am J Med 1991 91 142ndash50

144 KauffmanCA BradleySFRossSC et al Hepatosplenic candidia-

sis successful treatment with fluconazole Am J Med 1991 91 137ndash41

145 Kontoyiannis DP Luna MA Samuels BI et al Hepatosplenic can-

didiasis A manifestation of chronic disseminated candidiasis Infect Dis

Clin North Am 2000 14 721ndash39

146 Graninger W Presteril E Schneeweiss B et al Treatment of

Candida albicans fungaemia with fluconazole J Infect 1993 26 133ndash46

147 Phillips P Shafran S Garber G et al Multicenter randomized trial

of fluconazole versus amphotericin B for treatment of candidemia in

non-neutropenic patients Canadian Candidemia Study Group Eur J

Clin Microbiol Infect Dis 1997 16 337ndash45

148 Rex JH Bennett JE Sugar AM et alA randomized trial comparing

fluconazolewithamphotericinB for the treatmentof candidemia inpatients

without neutropenia Candidemia Study Group and the National Institute

N Engl J Med 1994 331 1325ndash30

149 Abele-Horn M Kopp A Sternberg U et al A randomized study

comparing fluconazolewith amphotericinB5-flucytosine for the treatment

of systemic Candida infections in intensive care patients Infection 1996

24 426ndash32

150 Nguyen MH Peacock JE Jr Tanner DC et al Therapeutic

approaches in patients with candidemia Evaluation in a multicenter

prospective observational study Arch Intern Med 1995 155 2429ndash35

151 Rex JH Pappas PG Karchmer AW et al A randomized and

blinded multicenter trial of high-dose fluconazole plus placebo versus flu-

conazole plus amphotericin B as therapy for candidemia and its con-

sequences in non-neutropenic subjectsClin Infect Dis 2003 36 1221ndash8

152 Mora-Duarte J Betts R Rotstein C et al Comparison of

caspofungin and amphotericin B for invasive candidiasis N Engl J Med

2002 347 2020ndash9

153 Sugar AM Saunders C Diamond RD et al Successful treatment

of Candida osteomyelitis with fluconazole A noncomparative study of

two patients Diagn Microbiol Infect Dis 1990 13 517ndash20

154 Tang C Successful treatment of Candida albicans osteomyelitis

with fluconazole J Infect 1993 26 89ndash92

155 LafontAOliveAGelmanMet alCandidaalbicansspondylodisci-

tis and vertebral osteomyelitis in patients with intravenous heroin drug

addiction Report of 3 new cases J Rheumatol 1994 21 953ndash6

156 Hennequin C Bouree P Hiesse C et al Spondylodiskitis due to

Candida albicans report of two patients who were successfully treated

with fluconazole and review of the literature Clin Infect Dis 1996 23176ndash8

157 Jonnalagadda S VeerabaguMP Rakela J et alCandida albicans

osteomyelitis in a liver transplant recipient a case report and review of the

literature Transplantation 1996 62 1182ndash4

158 Rossel P Schonheyder HC Nielsen H Fluconazole therapy

inCandidaalbicansspondylodiscitisScandJ InfectDis199830 527ndash30

159 TurnerDLJohnsonSARuleSASuccessful treatmentof candidal

osteomyelitis with fluconazole following failure with liposomal ampho-

tericin B J Infect 1999 38 51ndash3

160 El-Zaatari MM Hulten K Fares Y et al Successful treatment of

Candida albicans osteomyelitis of the spine with fluconazole and surgical

debridement case report J Chemother 2002 14 627ndash30

161 Seravalli L Van Linthoudt D Bernet C et al Candida glabrata

spinal osteomyelitis involving two contiguous lumbar vertebrae a case

report and review of the literature Diagn Microbiol Infect Dis 2003 45137ndash41

162 Garbino J Schnyder I LewDP et al An unusual cause of vertebral

osteomyelitis Candida species Scand J Infect Dis 2003 35 288ndash91

163 TunkelARThomasCYWispelweyBCandidaprostheticarthritis

report of a case treated with fluconazole and review of the literature Am J

Med 1993 94 100ndash3

Review

408

164 CushingRD FulgenziWR Synovial fluid levels of fluconazole in a

patient with Candida parapsilosis prosthetic joint infection who had an

excellent clinical response J Arthroplasty 1997 12 950

165 Fukasawa N Shirakura K Candida arthritis after total knee

arthroplastymdasha case of successful treatment without prosthesis removal

Acta Orthop Scand 1997 68 306ndash7

166 Lerch K Kalteis T Schubert T et al Prosthetic joint infections with

osteomyelitis due to Candida albicans Mycoses 2003 46 462ndash6

167 Clancy CJ Nguyen MH Morris AJ Candidal mediastinitis an

emerging clinical entity Clin Infect Dis 1997 25 608ndash13

168 PetrikkosGSkiadaA SabatakouH et al Case report Successful

treatment of two cases of post-surgical sternal osteomyelitis due to

Candida krusei and Candida albicans respectively with high doses of

triazoles (fluconazole itraconazole) Mycoses 2001 44 422ndash5

169 Weers-Pothoff GHavermans JF Kamphuis J et alCandida tropi-

calis arthritis in a patient with acutemyeloid leukemia successfully treated

with fluconazole case report and review of the literature Infection 1997

25 109ndash11

170 Laatikainen L TuominenM vonDickhoff K Treatment of endoge-

nous fungal endophthalmitis with systemic fluconazole with or without

vitrectomy Am J Ophthalmol 1992 113 205ndash7

171 Borne MJ Elliott JH OrsquoDay DM Ocular fluconazole treatment of

Candidaparapsilosisendophthalmitis after failed intravitreal amphotericin

B Arch Ophthalmol 1993 111 1326ndash7

172 Zarbin MA Becker E Witcher J et al Treatment of presumed

fungal endophthalmitis with oral fluconazole Ophthalmic Surg Lasers

1996 27 628ndash31

173 WongVK TasmanWEagleRC et al BilateralCandida parapsilo-

sis endophthalmitis Arch Ophthalmol 1997 115 670ndash2

174 Kauffman CA Bradley SF Vine AK Candida endophthalmitis

associated with intraocular lens implantation efficacy of fluconazole ther-

apy Mycoses 1993 36 13ndash17

175 del Palacio A Cuetara MS Ferro M et al Fluconazole in the man-

agement of endophthalmitis in disseminated candidosis of heroin addicts

Mycoses 1993 36 193ndash9

176 Luttrull JK Wan WL Kubak BM et al Treatment of ocular fungal

infections with oral fluconazole Am J Ophthalmol 1995 119 477ndash81

177 Akler ME Vellend H McNeely DM et al Use of fluconazole in the

treatment of candidal endophthalmitis Clin Infect Dis 1995 20 657ndash64

178 Christmas NJ Smiddy WE Vitrectomy and systemic fluconazole

for treatment of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1996 27 1012ndash18

179 EssmanTFFlynnHWSmiddyWEet al Treatment outcomes in a

10-year study of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1997 28 185ndash94

180 Martinez-Vazquez C Fernandez-Ulloa J Bordon J et al Candida

albicans endophthalmitis in brown heroin addicts response to early vit-

rectomyprecededand followedbyantifungal therapyClin InfectDis1998

27 1130ndash3

181 Aleixo MJ Caldeira L Ferreira ML Candida albicans meningitis

clinical case J Infect 2000 40 191ndash2

182 InoueY YozuR Ueda T et al A case report ofCandida parapsilo-

sis endocarditis J Heart Valve Dis 1998 7 240ndash2

183 Isalska BJ Stanbridge TN Fluconazole in the treatment of candi-

dal prosthetic valve endocarditis BMJ 1988 297 178ndash9

184 Martino P Meloni G Cassone A Candidal endocarditis and treat-

ment with fluconazole and granulocyte-macrophage colony-stimulating

factor Ann Intern Med 1990 112 966ndash7

185 Roupie E Darmon JY Brochard L et al Fluconazole therapy of

candidal native valveendocarditisEur JClinMicrobiol InfectDis199110458ndash9

186 Hernandez JA Gonzalez-Moreno M Llibre JM et al Candidal

mitral endocarditis and long-term treatment with fluconazole in a patient

with human immunodeficiency virus infection Clin Infect Dis 1992 151062ndash3

187 Venditti MDeBernardis FMicozzi A et al Fluconazole treatment

of catheter-related right-sided endocarditis caused by Candida albicans

and associated with endophthalmitis and folliculitis Clin Infect Dis 1992

14 422ndash6

188 Wallbridge DR McCartney AC Richardson MD Fluconazole in

the treatment ofCandidaprosthetic valveendocarditisMycoses199336259ndash61

189 Otaki M Kitamura N Candida prosthetic valve endocarditis An

autopsy review Int Surg 1993 78 252ndash3

190 Czwerwiec FS Bilsker MS Kamerman ML et al Long-term sur-

vival after fluconazole therapy of candidal prosthetic valve endocarditis

Am J Med 1993 94 545ndash6

191 Thakur RK Skelcy KM Kahn RN et al Successful treatment of

Candida prosthetic valve endocarditis with a combination of fluconazole

and amphotericin B Crit Care Med 1994 22 712ndash14

192 Cancelas JA Lopez JCabezudoE et al Native valve endocarditis

due toCandida parapsilosis a late complication after bonemarrow trans-

plantation-related fungemia Bone Marrow Transplant 1994 13 333ndash4

193 Zahid MA Klotz SA Hinthorn DR Medical treatment of recurrent

candidemia in a patient with probable Candida parapsilosis prosthetic

valve endocarditis Chest 1994 105 1597ndash8

194 Wells CJ Leech G Lever AM et al Treatment of native valve

Candida endocarditis with fluconazole J Infect 1995 31 233ndash5

195 Gilbert HM Peters ED Lang SJ et al Successful treatment of

fungal prosthetic valve endocarditis case report and review Clin Infect

Dis 1996 22 348ndash54

196 Nguyen MH Nguyen ML Yu VL et al Candida prosthetic valve

endocarditis prospective study of six cases and review of the literature

Clin Infect Dis 1996 22 262ndash7

197 Lejko-Zupanc T Kozelj M A case of recurrent Candida parapsilo-

sis prosthetic valve endocarditis cure bymedical treatment alone J Infect

1997 35 81ndash2

198 Joly V BelmatougN Leperre A et al Pacemaker endocarditis due

to Candida albicans case report and review Clin Infect Dis 1997 251359ndash62

199 Rex JH Walsh T Sobel JD et al Practice guidelines for the treat-

mentof candidiasis InfectiousDiseasesSocietyofAmericaClin InfectDis

2000 30 662ndash78

200 Baddour LM Long-term suppressive therapy for Candida para-

psilosis-induced prosthetic valve endocarditis Mayo Clin Proc 1995

70 773ndash5

201 Melgar GR Nasser RM Gordon SM Fungal prosthetic valve

endocarditis in 16 patients An 11-year experience in a tertiary care hos-

pital Medicine 1997 76 94ndash103

202 Dupont H Paugam-Burtz C Muller-Serieys C et al Predictive

factors of mortality due to polymicrobial peritonitis with Candida isolation

in peritoneal fluid in critically ill patients Arch Surg 2002 137 1341ndash6

203 Lee SC FungCP ChenHY et alCandida peritonitis due to peptic

ulcer perforation incidence rate risk factors prognosis and susceptibility

to fluconazole and amphotericin B Diagn Microbiol Infect Dis 2002 4423ndash7

204 Levine J Bernard DB Idelson BA et al Fungal peritonitis compli-

cating continuous ambulatory peritoneal dialysis successful treatment

with fluconazole a new orally active antifungal agent Am J Med 1989

86 825ndash7

205 Michel C Courdavault L al Khayat R et al Fungal peritonitis in

patients on peritoneal dialysis Am J Nephrol 1994 14 113ndash20

206 WangAYYuAWLi PKet al Factors predicting outcomeof fungal

peritonitis in peritoneal dialysis analysis of a 9-year experience of fungal

peritonitis in a single center Am J Kidney Dis 2000 36 1183ndash92

207 Hawkins JL Baddour LM Candida lusitaniae infections in the era

of fluconazole availability Clin Infect Dis 2003 36 14ndash18

Review

409

208 KauffmanCAVazquezJASobel JDetal Prospectivemulticenter

surveillance study of funguria in hospitalized patients The National Insti-

tute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group

Clin Infect Dis 2000 30 14ndash18

209 Sobel JD Kauffman CA McKinsey D et al Candiduria a random-

ized double-blind study of treatment with fluconazole and placebo The

National Institute of Allergy and Infectious Diseases (NIAID) Mycoses

Study Group Clin Infect Dis 2000 30 19ndash24

210 LundstromTSobel JNosocomial candiduria a reviewClin Infect

Dis 2001 32 1602ndash7

211 Kaufman D Boyle R Hazen KC et al Fluconazole prophylaxis

against fungal colonization and infection in preterm infants N Engl J

Med 2001 345 1660ndash6

212 Kicklighter SD Springer SC Cox T et al Fluconazole for the pro-

phylaxis against candidal rectal colonization in the very low birth weight

infant Pediatrics 2001 107 293ndash8

213 McGuire W Clerihew L Austin N Prophylactic intravenous anti-

fungal agents to prevent mortality and morbidity in very low birth weight

infants Cochrane Database Syst Rev 2004 CD003850

214 Agarwal JBansalSMalikGKetal Trends inneonatal septicemia

emergence of non-albicans Candida Indian Pediatr 2004 41 712ndash15

215 FasanoCOrsquoKeefe JGibbsD Fluconazole treatment of neonates

and infants with severe fungal infections not treatable with conventional

agents Eur J Clin Microbiol Infect Dis 1994 13 351ndash4

216 Wainer S Cooper PA Gouws H et al Prospective study of flu-

conazole therapy in systemicneonatal fungal infectionPediatr InfectDis J

1997 16 763ndash7

217 Huang YC Lin TY Lien RI et al Fluconazole therapy in neonatal

candidemia Am J Perinatol 2000 17 411ndash15

218 Huttova M Hartmanova I Kralinsky K et al Candida fungemia in

neonates treated with fluconazole report of forty cases including eight

with meningitis Pediatr Infect Dis J 1998 17 1012ndash15

219 Gurpinar AN Balkan E Kilic N et al Fluconazole treatment of

neonates and infants with severe fungal infections J Int Med Res 1997

25 214ndash18

220 Driessen M Ellis JB Muwazi F et al The treatment of systemic

candidiasis in neonates with oral fluconazole Ann Trop Pediatr 1997 17263ndash71

221 Driessen M Ellis JB Cooper PA et al Fluconazole vs

amphotericin B for the treatment of neonatal fungal septicemia

a prospective randomized trial Pediatr Infect Dis J 1997 151107ndash12

222 Marr B Gross S Cunningham C et al Candidal sepsis and

meningitis in a very-low-birth-weight infant successfully treated with flu-

conazole and flucytosine Clin Infect Dis 1994 19 795ndash6

223 Oleinik EM Della-Latta P Rinaldi MG et al Candida lusitaniae

osteomyelitis in a premature infant Am J Perinatol 1993 10 313ndash15

224 Mondal RK Singhi SC Chakrabarti A Randomized comparison

between fluconazole and itraconazole for the treatment of candidemia in a

pediatric intensive care unit a preliminary study Pediatr Crit Care Med

2004 5 561ndash5

225 Viscoli C Castagnola E Fioredda F et al Fluconazole in the treat-

ment of candidiasis in immunocompromised children Antimicrob Agents

Chemother 1991 35 365ndash7

226 Decruyenaere J Colardyn F Vogelaers D et al Combined use of

fluconazole and selective digestive decontamination in the prevention of

fungal infection after adult liver transplantation Transplant Proc 1995 273515ndash16

227 Koh LP Kurup A Goh YT et al Randomized trial of fluconazole

versus low-dose amphotericin B in prophylaxis against fungal infections in

patients undergoing hematopoietic stem cell transplantationAmJHema-

tol 2002 71 260ndash7

228 Gluckman E Esperou-Bourdeau H Ribaud P et al Comparaison

entre le fluconazole et le ketoconazole pour la prophylaxie des infections

fongiques chez les patients traites par greffe de moelle allogenique Cah

Oncol 1993 2 167ndash9

Review

410

4 Vanrsquot Wout JW deGraeff-Meeder ER Paul LC et al Treatment of

two cases of cryptococcal meningitis with fluconazole Scand J Infect Dis

1988 20 193ndash8

5 Tucker RM Williams PL Arathoon EG et al Pharmacokinetics of

fluconazole in cerebrospinal fluid and serum in human coccidioidal

meningitis Antimicrob Agents Chemother 1988 32 369ndash73

6 ByrneWRWajszczukCPCryptococcalmeningitis in theacquired

immunodeficiency syndrome (AIDS) successful treatment with flucona-

zole after failure of amphotericin B Ann Intern Med 1988 108 384ndash5

7 HughesCE BeggsWH Action of fluconazole (UK-49858) in rela-

tion to other systemic antifungal azoles J Antimicrob Chemother 1987

19 171ndash4

8 DebruyneDClinicalpharmacokineticsof fluconazole insuperficial

and systemic mycoses Clin Pharmacokinet 1997 33 52ndash77

9 Brammer KW Coates PE Pharmacokinetics of fluconazole in

pediatric patients Eur J Clin Microbiol Infect Dis 1994 13 325ndash9

10 Schwarze R Penk A Pittrow L Administration of fluconazole in

children below 1 year of age Mycoses 1999 42 3ndash16

11 Schwarze R Penk A Pittrow L Treatment of candidal infections

with fluconazole in neonates and infants Eur J Med Res 2000 5 203ndash8

12 Thaler FBernardBTodMet al Fluconazolepenetration in cereb-

ral parenchyma in humans at steady stateAntimicrob Agents Chemother

1995 5 1154ndash6

13 Bozzette SA Gordon RL Yen A et al Biliary concentrations of

fluconazole in a patient with candidal cholecystitis case reportClin Infect

Dis 1992 4 701ndash3

14 Debruyne D Ryckelynck JP Moulin M et al Pharmacokinetics of

fluconazole in patients undergoing continuous ambulatory peritoneal dial-

ysis Clin Pharmacokinet 1990 18 491ndash8

15 Tod M Lortholary O Padoin C et al Intravenous penetration of

fluconazole during endophthalmitis Clin Microbiol Infect 1997 3 143ndash4

16 Urbak SF Degn T Fluconazole in the management of fungal ocu-

lar infections Ophthalmologica 1994 3 147ndash56

17 Fasano C OrsquoKeefe J Gibbs D Fluconazole treatment of children

with severe fungal infections not treatable with conventional agentsEur J

Clin Microbiol Infect Dis 1994 13 344ndash7

18 Aleck KA Bartley DL Multiple malformation syndrome following

fluconazole use in pregnancy report of an additional patient Am J Med

Genet 1997 72 253ndash6

19 Buijk SL Gyssens IC Mouton JW et al Pharmacokinetics of

sequential intravenous and enteral fluconazole in critically ill surgical

patients with invasive mycoses and compromised gastro-intestinal func-

tion Intensive Care Med 2001 27 115ndash21

20 El-Yazigi AEllisMErnstPet al Pharmacokinetics of oral flucona-

zole when used for prophylaxis in bone marrow transplant recipients

Antimicrob Agents Chemother 1997 41 914ndash17

21 Finch CK Green CA Self TH Fluconazole-carbamazepine inter-

action South Med J 2002 95 1099ndash100

22 Tucker RM Denning DW Hanson RH et al Interaction of azoles

with rifampin phenytoin and carbamazepine in vitro and clinical obser-

vations Clin Infect Dis 1992 14 165ndash74

23 Stockley IH Stockleyrsquos Drug Interactions A Source Book of Inter-

actions Their Mechanisms Clinical Importance and Management 6th

edn London UK Pharmaceutical Press 2002

24 von Moltke LL Greenblatt DJ Duan SX et al Inhibition of terfena-

dine metabolism in vitro by azole antifungal agents and by selective sero-

tonin reuptake inhibitor antidepressants relation to pharmacokinetic

interactions in vivo J Clin Psychopharmacol 1996 16 104ndash12

25 BrockmeyerNH Tillmann I Mertins L et al Pharmacokinetic inter-

action of fluconazole and zidovudine in HIV-positive patients Eur J Med

Res 1997 2 377ndash83

26 van Burik JA LeisenringW Myerson D et al The effect of prophy-

lactic fluconazole on the clinical spectrum of fungal diseases in bone

marrow transplant recipients with special attention to hepatic candidiasis

An autopsy study of 355 patients Medicine 1998 77 246ndash54

27 Wingard JR Antifungal chemoprophylaxis after blood andmarrow

transplantation Clin Infect Dis 2002 34 1386ndash90

28 GarbinoJLewDPRomandJAetalPreventionofsevereCandida

infections in nonneutropenic high-risk critically ill patients a randomized

double-blind placebo-controlled trial in patients treatedbyselectivediges-

tive decontamination Intensive Care Med 2002 28 1708ndash17

29 Gearhart MO Worsening of liver function with fluconazole and

review of azole antifungal hepatotoxicity Ann Pharmacother 1994 281177ndash81

30 Crerar-Gilbert A Boots R Fraenkel D et al Survival following ful-

minant hepatic failure from fluconazole induced hepatitis Anaesth Inten-

sive Care 1999 27 650ndash2

31 PappasPGKauffmanCAPerfect Jetal Alopeciaassociatedwith

fluconazole therapy Ann Intern Med 1995 123 354ndash7

32 Stevens DA Diaz M Negroni R et al Safety evaluation of chronic

fluconazole therapy Fluconazole Pan-American Study Group

Chemotherapy 1997 5 371ndash7

33 Anaissie EJ Kontoyiannis DP Huls C et al Safety plasma con-

centrations and efficacy of high-dose fluconazole in invasive mold infec-

tions J Infect Dis 1995 172 599ndash602

34 Gussenhoven MJ Haak A Peereboom-Wynia JD et al Stevens-

Johnson syndrome after fluconazole Lancet 1991 338 120

35 NovelliVHolzelHSafetyand tolerabilityof fluconazole inchildrenAntimicrob Agents Chemother 1999 43 1955ndash60

36 Koks CH Crommentuyn KM Hoetelmans RM et al Can

fluconazole concentrations in saliva be used for therapeutic drug mon-

itoring Ther Drug Monit 2001 4 449ndash53

37 Louie A Drusano GL Banerjee P et al Pharmacodynamics of

fluconazole in amurinemodel of systemic candidiasisAntimicrob Agents

Chemother 1998 42 1105ndash9

38 PittrowLPenkAPlasmaand tissueconcentrationsof fluconazole

and their correlation to breakpoints Mycoses 1997 40 25ndash32

39 Rex JH Pfaller MA Galgiani JN et al Development of interpretive

breakpoints forantifungalsusceptibility testing conceptual frameworkand

analysis of in vitro-in vivo correlation data for fluconazole itraconazole

and Candida infections Subcommittee on Antifungal Susceptibility Test-

ingof theNationalCommittee forClinical LaboratoryStandardsClin Infect

Dis 1997 24 235ndash47

40 Pfaller MA Diekema DJ Twelve years of fluconazole in clinical

practiceglobal trends inspeciesdistributionand fluconazolesusceptibility

of bloodstream isolatesofCandida International FungalSurveillancePar-

ticipant Group Clin Microbiol Infect 2004 10 Suppl 1 11ndash23

41 Tortorano AM Rigoni AL Biraghi E et al The European Confed-

eration of Medical Mycology (ECMM) survey of candidaemia in Italy anti-

fungal susceptibility patterns of 261 non-albicans Candida isolates from

blood J Antimicrob Chemother 2003 52 679ndash82

42 Pfaller MAMesser SA Boyken L et al Geographic variation in the

susceptibilities of invasive isolates of Candida glabrata to seven systemi-

cally active antifungal agents a global assessment from the ARTEMIS

Antifungal Surveillance Program conducted in 2001 and 2002 J Clin

Microbiol 2004 42 3142ndash6

43 Paya CV Fungal infections in solid-organ transplantation Clin

Infect Dis 1993 16 677ndash88

44 Singh N Wagener MM Marino IR et al Trends in invasive fungal

infections in liver transplant recipients correlation with evolution in trans-

plantation practices Transplantation 2002 73 63ndash7

45 Fung JJ Fungal infection in liver transplantation Transplant InfectDis 2002 4 18ndash23

46 Winston DJ Pakrasi A Busuttil RW Prophylactic fluconazole in

liver transplant recipientsA randomized double-blind placebo-controlled

trial Ann Intern Med 1999 131 729ndash37

47 Gladdy RA Richardson SE Davies HD et al Candida infection in

pediatric liver transplant recipients Liver Transpl Surg 1999 5 16ndash24

Review

405

48 Castaldo P Stratta RJ Wood RP et al Clinical spectrum of fungal

infections after orthotopic liver transplantation Arch Surg 1991 126149ndash56

49 Husain S Tollemar J Dominguez EA et al Changes in the spec-

trum and risk factors for invasive candidiasis in liver transplant recipients

prospective multicenter case-controlled study Transplantation 2003

75 2023ndash9

50 GeorgeMJ Snydman DRWerner BG et al The independent role

of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic

liver transplant recipients Boston Center for Liver Transplantation

CMVIG-Study Group Cytogam MedImmune Inc Gaithersburg Mary-

land Am J Med 1997 103 106ndash13

51 Dockrell DH Mendez JC Jones M et al Human herpesvirus 6

seronegativity before transplantation predicts the occurrence of fungal

infection in liver transplant recipientsTransplantation 1999 67 399ndash403

52 Tollemar J Ericzon BG Barkholt L et al Risk factors for deep

Candida infections in liver transplant recipients Transplant Proc 1990

22 1826ndash7

53 Lumbreras C Cuervas-Mons V Jara P et al Randomized trial of

fluconazole versus nystatin for the prophylaxis of Candida infection

following liver transplantation J Infect Dis 1996 174 583ndash8

54 Winston DJ Busuttil RW Randomized controlled trial of oral itra-

conazole solution versus intravenousoral fluconazole for prevention of

fungal infections in liver transplant recipients Transplantation 2002

74 688ndash95

55 Tortorano AM Viviani MA PaganoA et al Candida colonization in

orthotopic liver tranplantation fuconazole versus oral amphoericin B

J Mycol Med 1995 5 21ndash4

56 Kung N Fisher N Gunson B et al Fluconazole prophylaxis for

high-risk liver transplant recipients Lancet 1995 345 1234ndash5

57 Pappas PG Rex JH Sobel JD et al Guidelines for treatment of

candidiasis Clin Infect Dis 2004 38 161ndash89

58 PayaCV Prevention of fungal infection in transplantation TransplInfect Dis 2002 4 S46ndash51

59 LortholaryO Dupont B Antifungal prophylaxis during neutropenia

and immunodeficiency Clin Microbiol Rev 1997 10 477ndash504

60 Benedetti E Gruessner AC Troppmann C et al Intra-abdominal

fungal infections after pancreatic transplantation incidence treatment

and outcome J Am Coll Surg 1996 183 307ndash16

61 LumbrerasC Fernandez I Velosa J et al Infectious complications

following pancreatic transplantation incidence microbiological and clini-

cal characteristics and outcome Clin Infect Dis 1995 20 514ndash20

62 Patterson JE Epidemiology of fungal infections in solid organ

transplant patients Transpl Infect Dis 1999 1 229ndash36

63 Kusne S Furukawa H Abu-Elmagd K et al Infectious complica-

tions after small bowel transplantation in adults an update Transplant

Proc 1996 28 2761ndash2

64 Paterson DL Ndirangu M Kwak EJ et al Opportunistic infections

in solid-organ transplant recipients pre-treated with alumetuzumab In

Abstracts of the Forty-Fourth Interscience Conference on Antimicrobial

Agents and Chemotherapy Washington DC 2004 Abstract K-1427 p

357 American Society for Microbiology Washington DC USA

65 Kramer MR Marshall SE Starnes VA et al Infectious complica-

tions in heart-lung transplantation Analysis of 200 episodes Arch Intern

Med 1993 153 2010ndash6

66 Goodrich JMReedECMori M et al Clinical features and analysis

of risk factors for invasive candidal infection after marrow transplantation

J Infect Dis 1991 164 731ndash40

67 Dykewicz CA Centers for Disease Control and Prevention (US)

Infectious Diseases Society of America American Society of Blood and

MarrowTransplantation Summary of the guidelines for preventing oppor-

tunistic infections among hematopoietic stem cell transplant recipients

Clin Infect Dis 2001 33 139ndash44

68 Sable CA Donowitz GR Infections in bone marrow transplant

recipients Clin Infect Dis 1994 18 273ndash81

69 Goodman JLWinston DJ Greenfield RA et al A controlled trial of

fluconazole to prevent fungal infections in patients undergoing bone mar-

row transplantation N Engl J Med 1992 326 845ndash51

70 Slavin MA Osborne B Adams R et al Efficacy and safety of flu-

conazole prophylaxis for fungal infectionsaftermarrow transplantationmdasha

prospective randomized double-blind study J Infect Dis 1995 1711545ndash52

71 Marr KA Seidel K SlavinMA et al Prolonged fluconazole prophy-

laxis is associated with persistent protection against candidiasis-related

death in allogeneic marrow transplant recipients long-term follow-up of a

randomized placebo-controlled trial Blood 2000 96 2055ndash61

72 AlangadenGChandrasekar PH BaileyE et al Antifungal prophy-

laxis with low-dose fluconazole during bone marrow transplantation The

Bone Marrow Transplantation Team Bone Marrow Transplant 1994 14919ndash24

73 Wolff SN Fay J Stevens D et al Fluconazole versus low-dose

amphotericin B for the prevention of fungal infections in patients under-

going bonemarrow transplantation a study of theNorthAmericanMarrow

Transplant Group Bone Marrow Transplant 2000 25 853ndash9

74 Annaloro C Oriana A Tagliaferri E et al Efficacy of different pro-

phylactic antifungal regimens in bone marrow transplantation Haemato-

logica 1995 80 512ndash17

75 Winston DJ Maziarz RT Chandrasekar PH et al Intravenous and

oral itraconazole versus intravenous and oral fluconazole for long-term

antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant

recipients A multicenter randomized trial Ann Intern Med 2003 138705ndash13

76 MarrKACrippaF LeisenringWet al Itraconazoleversus flucona-

zole forpreventionof fungal infections inpatients receivingallogeneicstem

cell transplants Blood 2004 103 1527ndash33

77 MacMillan ML Goodman JL DeFor TE et al Fluconazole to pre-

vent yeast infections in bone marrow transplantation patients a random-

ized trial of high versus reduced dose and determination of the value of

maintenance therapy Am J Med 2002 112 369ndash79

78 Marr KA Seidel K White TC et al Candidemia in allogeneic blood

and marrow transplant recipients evolution of risk factors after the adop-

tion of prophylactic fluconazole J Infect Dis 2000 181 309ndash16

79 van Burik JA Ratanatharathorn V Stepan DE et al Micafungin

versus fluconazole for prophylaxis against invasive fungal infections dur-

ing neutropenia in patients undergoing hematopoietic stem cell trans-

plantation Clin Infect Dis 2004 39 1407ndash16

80 Prentice HG Kibbler CC Prentice AG Towards a targeted risk-

based antifungal strategy in neutropenic patients Br J Haematol 2000

110 273ndash84

81 Laverdiere M Rotstein C Bow EJ et al Impact of fluconazole

prophylaxis on fungal colonizatin and infection rates in neutropenic

patients The Canadian Fluconazole Study J Animicrob Chemother

2000 46 1001ndash8

82 Winston DJ Chandrasekar PH Lazarus HM et al Fluconazole

prophylaxis of fungal infections in patients with acute leukemia Results

of a randomized placebo-controlled double-blind multicenter trial Ann

Intern Med 1993 118 495ndash503

83 Chandrasekar PHGatnyCMEffect of fluconazole prophylaxis on

fever and use of amphotericin in neutropenic cancer patients Bone Mar-

row Transplantation Team Chemotherapy 1994 40 136ndash43

84 Rotstein C Bow EJ Laverdiere M et al Randomized placebo-

controlled trial of fluconazole prophylaxis for neutropenic cancer patients

benefit basedonpurposeand intensity of cytotoxic therapy TheCanadian

Fluconazole Prophylaxis Study Group Clin Infect Dis 1999 28 331ndash40

85 YamacK Senol E HaznedarR Prophylactic use of fluconazole in

neutropenic cancer patients Postgrad Med J 1997 71 284ndash6

86 KernW BehreG Rudolf T et al Failure of fluconazole prophylaxis

to reducemortality or the requirement of systemic amphotericin B therapy

during treatment for refractory acute myeloid leukemia results of a

Review

406

prospective randomized phase III study German AML Cooperative

Group Cancer 1998 83 291ndash301

87 SchaffnerA SchaffnerM Effect of prophylactic fluconazole on the

frequencyof fungal infectionsamphotericinBuseandhealthcarecosts in

patients undergoing intensive chemotherapy for hematologic neoplasias

J Infect Dis 1995 172 1035ndash41

88 Egger T Gratwohl A Tichelli A et al Comparison of fluconazole

with oral polyenes in the prevention of fungal infections in neutropenic

patients A prospective randomized single-center study Support Care

Cancer 1995 3 139ndash46

89 Morgenstern GR Prentice AG Prentice H et al A randomized

controlled trial of itraconazole versus fluconazole for the prevention of

fungal infections in patients with haematological malignancies UK Mul-

ticentre Antifungal Prophylaxis Study Group Br J Haematol 1999 105901ndash11

90 EllisMEClinkHErnstPetalControlledstudyof fluconazole in the

preventionof fungal infections in neutropenic patientswith haematological

malignancies and bone marrow transplant recipients Eur J Clin Microbiol

Infect Dis 1994 13 3ndash11

91 Philpott-Howard JN Wade JJ Mufti GJ et al Randomized com-

parisonoforal fluconazoleversusoralpolyenes for thepreventionof fungal

infection in patients at risk of neutropenia Multicentre Study Group

J Antimicrob Chemother 1993 31 973ndash84

92 Ninane J A multicentre study of fluconazole versus oral polyenes

in the prevention of fungal infection in children with hematological or

oncological malignancies Multicentre Study Group Eur J Clin Microbiol

Infect Dis 1994 13 330ndash7

93 Menichetti F Del Favero A Martino P et al Preventing fungal

infection in neutropenic patients with acute leukemia fluconazole com-

pared with oral amphotericin B The GIMEMA Infection Program Ann

Intern Med 1994 120 913ndash18

94 Akiyama H Mori S Tanikawa S et al Fluconazole versus oral

amphotericin B in preventing fungal infection in chemotherapy-induced

neutropenic patients with haematological malignancies Mycoses 1996

36 373ndash8

95 Meunier F AounM JanssensM et al Chemoprophylaxis of fungal

infections in granulocytopenic patients using fluconazole versus oral

amphotericin B Drug Invest 1991 3 258ndash65

96 Rozenberg-Arska M Dekker AW Branger J et al A randomized

study to compare oral fluconazole to amphotericin B in the prevention of

fungal infections inpatientswithacute leukaemiaJAntimicrobChemother

1991 27 369ndash76

97 Brammer KW Management of fungal infection in neutropenic

patients with fluconazole Haematol Blood Transfus 1990 33 546ndash50

98 Bodey GP Anaissie EJ Elting LS et al Antifungal prophylaxis

during remission induction therapy for acute leukemia fluconazole versus

intravenous amphotericin B Cancer 1994 73 2099ndash106

99 Kanda Y Yamamoto R Chizuka A et al Prophylactic action of

oral fluconazole against fungal infection in neutropenic patients A

meta-analysis of 16 randomized controlled trials Cancer 2000 891611ndash25

100 Bow EJ Laverdiere M Lussier N et al Antifungal prophylaxis for

severely neutropenic chemotherapy recipients a meta analysis of

randomized-controlled clinical trials Cancer 2002 94 3230ndash46

101 Viscoli C Paesmans M Sanz M et al Association between

antifungal prophylaxis and rate of documented bacteremia in febrile

neutropenic cancer patients Clin Infect Dis 2001 32 1532ndash7

102 HughesWT Armstrong D BodeyGP et al 2002 guidelines for the

use of antimicrobial agents in neutropenic patients with cancerClin Infect

Dis 2002 34 730ndash51

103 Cornely OA Bohme A Buchheidt D et al Prophylaxis of invasive

fungal infections in patients with hematological malignancies and solid

tumorsmdashguidelines of the Infectious Diseases Working Party (AGIHO)

of the German Society of Hematology and Oncology (DGHO) Ann

Hematol 2003 82 Suppl 2 186ndash200

104 McNeil MM Nash SL Hajjeh RA et al Trends in mortality due to

invasivemycotic diseases in theUnitedStates 1980ndash1997Clin InfectDis

2001 33 641ndash7

105 KibblerCCSeatonSBarnesRA et alManagement and outcome

of bloodstream infections due to Candida species in England and Wales

J Hosp Infect 2003 54 18ndash24

106 Marchetti O Bille J Fluckiger U et al Fungal Infection Network of

Switzerland Epidemiology of candidemia in Swiss tertiary care hospitals

secular trends 1991-2000 Clin Infect Dis 2004 38 311ndash20

107 Gudlaugsson O Gillespie S Lee K et al Attributable mortality of

nosocomial candidemia revisited Clin Infect Dis 2003 37 1172ndash7

108 Ibanez-Nolla J Nolla-Salas M Leon MA et al Early diagnosis of

candidiasis in nonneutropenic critically ill patients J Infect 2004 48181ndash92

109 BlumbergHMJarvisWRSoucieJMetalRisk factors for candidal

bloodstream infections in surgical intensive care unit patients the NEMIS

prospective multicenter study The National Epidemiology of Mycosis

Survey Clin Infect Dis 2001 33 177ndash86

110 Pittet D Monod M Suter PM et al Candida colonization and

subsequent infections in critically ill surgical patients Ann Surg 1994

220 751ndash8

111 Sendid B Poirot JL Tabouret M et al Combined detection of

mannanaemia and antimannan antibodies as a strategy for the diagnosis

of systemic infectioncausedbypathogenicCandidaspeciesJMedMicro-

biol 2002 51 433ndash42

112 Bar W Hecker H Diagnosis of systemic Candida infections in

patients of the intensive care unit Significance of serum antigens and

antibodies Mycoses 2002 45 22ndash8

113 Calandra T Marchetti O Clinical trials of antifungal prophy-

laxis among patients undergoing surgery Clin Infect Dis 2004 39S185ndash92

114 Sypula WT Kale-Pradhan PB Therapeutic dilemma of flucona-

zole prophylaxis in intensive care Ann Pharmacother 2002 36 155ndash9

115 Pelz RK Hendrix CW Swoboda SM et al Double-blind placebo-

controlled trial of fluconazole to prevent candidal infections in critically ill

surgical patients Ann Surg 2001 233 542ndash8

116 Eggimann P Francioli P Bille J et al Fluconazole prophylaxis

prevents intraabdominal candidiasis in high-risk surgical patients Crit

Care Med 1997 27 1066ndash72

117 Swoboda SM Merz WG Lipsetta PA Candidemia the impact of

antifungal prophylaxis in a surgical intensive care unitSurg Infect20034345ndash54

118 Todd JC OrsquoNeal VG Grady KP et al Reduction of secondary

mycotic infections in the trauma intensivie care unit with fluconazole

J Trauma 1991 31 1722ndash27

119 Jacobs S Price Evans DA Tariq M et al Fluconazole improves

survival in septic shock a randomized double-blind prospective studyCrit

Care Med 2003 31 1938ndash46

120 Zervos EE Fink GW Norman JG et al Fluconazole increases

bactericidal activity of neutrophils through non-cytokine-mediated path-

way J Trauma 1996 41 465ndash70

121 AblesAZBlumerNAValainisGTetal Fluconazoleprophylaxis of

severe Candida infection in trauma and postsurgical patients a prospec-

tive double-blind randomised placebo-controlled trial Infect Dis Clin

Pract 2000 9 169ndash75

122 Kam LW Lin JD Management of systemic candidal infections in

the intensive care unit Am J Health Syst Pharm 2002 59 33ndash41

123 Rocco TR Reinert SE Simms HH Effects of fluconazole admin-

istration in critically ill patients analysis of bacterial and fungal resistance

Arch Surg 2000 135 160ndash5

124 Tortorano AM Caspani L Rigoni AL et al Candidosis in the inten-

sive care unit a 20-year survey J Hosp Infect 2004 57 8ndash13

125 EggimannPGarbino J Pittet DManagement ofCandida species

infections in critically ill patients Lancet Infect Dis 2003 3 772ndash85

Review

407

126 EggimannPGarbinoJPittetDEpidemiologyofCandida species

infections incritically ill non-immunosuppressedpatientsLancet InfectDis

2003 3 685ndash702

127 Martins MD Lozano-Chiu M Rex JH Declining rates of oropha-

ryngeal candidiasis and carriage of Candida albicans associated with

trends toward reduced rates of carriage of fluconazole-resistant C albi-

cans in human immunodeficiency virus-infected patients Clin Infect Dis

1998 27 1291ndash4

128 Powderly WG Finkelstein D Feinberg J et al A randomized trial

comparing fluconazole with clotrimazole troches for the prevention of fun-

gal infections in patients with advanced human immunodeficiency virus

infection NIAID AIDS Clinical Trials Group N Engl J Med 1995 332700ndash5

129 Leen CL Dunbar EM Ellis ME et al Once-weekly fluconazole to

prevent recurrenceof oropharyngeal candidiasis inpatientswithAIDSand

AIDS-related complex a double-blind placebo-controlled study J Infect

1990 21 55ndash60

130 Stevens DA Greene SI Lang OS Thrush can be prevented in

patients with acquired immunodeficiency syndrome and the acquired

immunodeficiency syndrome-related complex Randomized double-

blind placebo-controlled study of 100-mg oral fluconazole daily Arch

Intern Med 1991 151 2458ndash64

131 Just-Nubling G Gentschew G Meissner K Fluconazole prophy-

laxis of recurrent oral candidiasis inHIV-positive patientsEur JClinMicro-

biol Infect Dis 1991 10 917ndash21

132 Marriott DJ Jones PD Hoy JF et al Fluconazole once a week as

secondary prophylaxis against oropharyngeal candidiasis in HIV-infected

patients A double-blind placebo-controlled studyMed J Aust 1993 158312ndash16

133 Schuman P Capps L Peng G et al Weekly fluconazole for the

prevention ofmucosal candidiasis inwomenwithHIV infection A random-

ized double-blind placebo-controlled trial Terry Beirn Community Pro-

grams for Clinical Research on AIDSAnn InternMed 1997 126 689ndash96

134 Havlir DV DubeMPMcCutchan JA et al Prophylaxis with weekly

versus daily fluconazole for fungal infections in patients with AIDS Clin

Infect Dis 1998 27 1369ndash75

135 Pagani JL Chave JP Casjka C et al Efficacy tolerability and

development of resistance in HIV-positive patients treated with flucona-

zole for secondary prevention of oropharyngeal candidiasis a random-

ized double-blind placebo-controlled trial JAntimicrobChemother 2002

50 231ndash40

136 Vazquez JA Peng G Sobel JD et al Evolution of antifungal sus-

ceptibility amongCandidaspecies isolates recovered fromhuman immun-

odeficiency virus-infected women receiving fluconazole prophylaxis Clin

Infect Dis 2001 33 1069ndash75

137 Delfraissy JF Prise en charge therapeutique des patients infectespas le VIH Rapport Delfraissy Paris Flammarion 2004

138 DePauwBERaemaekers JMDonnelly JPet al Anopenstudyon

the safety and efficacy of fluconazole in the treatment of disseminated

Candida infections in patients treated for hematological malignancy Ann

Hematol 1995 70 83ndash7

139 Anaissie EJ Vartivarian SE Abi-Said D et al Fluconazole versus

amphotericin B in the treatment of hematogenous candidiasis a matched

cohort study Am J Med 1996 101 170ndash6

140 Anaissie EJ Darouiche RO Abi-Said D et al Management of

invasive candidal infections results of a prospective randomized multi-

center study of fluconazole versus amphotericin B and review of the

literature Clin Infect Dis 1996 23 964ndash72

141 Myoken Y Kyo T Kohara T et al Breakthrough fungemia caused

by azole-resistant Candida albicans in neutropenic patients with acute

leukemia Clin Infect Dis 2003 36 1496ndash7

142 Anttila VJ FarkkilaM JanssonSE et al Diagnostic laparoscopy in

patientswith acute leukemiaandsuspectedhepatic candidiasisEur JClin

Microbiol Infect Dis 1997 16 637ndash43

143 Anaissie E Bodey GP Kantarjian H et al Fluconazole therapy for

chronic disseminated candidiasis in patients with leukemia and prior

amphotericin B therapy Am J Med 1991 91 142ndash50

144 KauffmanCA BradleySFRossSC et al Hepatosplenic candidia-

sis successful treatment with fluconazole Am J Med 1991 91 137ndash41

145 Kontoyiannis DP Luna MA Samuels BI et al Hepatosplenic can-

didiasis A manifestation of chronic disseminated candidiasis Infect Dis

Clin North Am 2000 14 721ndash39

146 Graninger W Presteril E Schneeweiss B et al Treatment of

Candida albicans fungaemia with fluconazole J Infect 1993 26 133ndash46

147 Phillips P Shafran S Garber G et al Multicenter randomized trial

of fluconazole versus amphotericin B for treatment of candidemia in

non-neutropenic patients Canadian Candidemia Study Group Eur J

Clin Microbiol Infect Dis 1997 16 337ndash45

148 Rex JH Bennett JE Sugar AM et alA randomized trial comparing

fluconazolewithamphotericinB for the treatmentof candidemia inpatients

without neutropenia Candidemia Study Group and the National Institute

N Engl J Med 1994 331 1325ndash30

149 Abele-Horn M Kopp A Sternberg U et al A randomized study

comparing fluconazolewith amphotericinB5-flucytosine for the treatment

of systemic Candida infections in intensive care patients Infection 1996

24 426ndash32

150 Nguyen MH Peacock JE Jr Tanner DC et al Therapeutic

approaches in patients with candidemia Evaluation in a multicenter

prospective observational study Arch Intern Med 1995 155 2429ndash35

151 Rex JH Pappas PG Karchmer AW et al A randomized and

blinded multicenter trial of high-dose fluconazole plus placebo versus flu-

conazole plus amphotericin B as therapy for candidemia and its con-

sequences in non-neutropenic subjectsClin Infect Dis 2003 36 1221ndash8

152 Mora-Duarte J Betts R Rotstein C et al Comparison of

caspofungin and amphotericin B for invasive candidiasis N Engl J Med

2002 347 2020ndash9

153 Sugar AM Saunders C Diamond RD et al Successful treatment

of Candida osteomyelitis with fluconazole A noncomparative study of

two patients Diagn Microbiol Infect Dis 1990 13 517ndash20

154 Tang C Successful treatment of Candida albicans osteomyelitis

with fluconazole J Infect 1993 26 89ndash92

155 LafontAOliveAGelmanMet alCandidaalbicansspondylodisci-

tis and vertebral osteomyelitis in patients with intravenous heroin drug

addiction Report of 3 new cases J Rheumatol 1994 21 953ndash6

156 Hennequin C Bouree P Hiesse C et al Spondylodiskitis due to

Candida albicans report of two patients who were successfully treated

with fluconazole and review of the literature Clin Infect Dis 1996 23176ndash8

157 Jonnalagadda S VeerabaguMP Rakela J et alCandida albicans

osteomyelitis in a liver transplant recipient a case report and review of the

literature Transplantation 1996 62 1182ndash4

158 Rossel P Schonheyder HC Nielsen H Fluconazole therapy

inCandidaalbicansspondylodiscitisScandJ InfectDis199830 527ndash30

159 TurnerDLJohnsonSARuleSASuccessful treatmentof candidal

osteomyelitis with fluconazole following failure with liposomal ampho-

tericin B J Infect 1999 38 51ndash3

160 El-Zaatari MM Hulten K Fares Y et al Successful treatment of

Candida albicans osteomyelitis of the spine with fluconazole and surgical

debridement case report J Chemother 2002 14 627ndash30

161 Seravalli L Van Linthoudt D Bernet C et al Candida glabrata

spinal osteomyelitis involving two contiguous lumbar vertebrae a case

report and review of the literature Diagn Microbiol Infect Dis 2003 45137ndash41

162 Garbino J Schnyder I LewDP et al An unusual cause of vertebral

osteomyelitis Candida species Scand J Infect Dis 2003 35 288ndash91

163 TunkelARThomasCYWispelweyBCandidaprostheticarthritis

report of a case treated with fluconazole and review of the literature Am J

Med 1993 94 100ndash3

Review

408

164 CushingRD FulgenziWR Synovial fluid levels of fluconazole in a

patient with Candida parapsilosis prosthetic joint infection who had an

excellent clinical response J Arthroplasty 1997 12 950

165 Fukasawa N Shirakura K Candida arthritis after total knee

arthroplastymdasha case of successful treatment without prosthesis removal

Acta Orthop Scand 1997 68 306ndash7

166 Lerch K Kalteis T Schubert T et al Prosthetic joint infections with

osteomyelitis due to Candida albicans Mycoses 2003 46 462ndash6

167 Clancy CJ Nguyen MH Morris AJ Candidal mediastinitis an

emerging clinical entity Clin Infect Dis 1997 25 608ndash13

168 PetrikkosGSkiadaA SabatakouH et al Case report Successful

treatment of two cases of post-surgical sternal osteomyelitis due to

Candida krusei and Candida albicans respectively with high doses of

triazoles (fluconazole itraconazole) Mycoses 2001 44 422ndash5

169 Weers-Pothoff GHavermans JF Kamphuis J et alCandida tropi-

calis arthritis in a patient with acutemyeloid leukemia successfully treated

with fluconazole case report and review of the literature Infection 1997

25 109ndash11

170 Laatikainen L TuominenM vonDickhoff K Treatment of endoge-

nous fungal endophthalmitis with systemic fluconazole with or without

vitrectomy Am J Ophthalmol 1992 113 205ndash7

171 Borne MJ Elliott JH OrsquoDay DM Ocular fluconazole treatment of

Candidaparapsilosisendophthalmitis after failed intravitreal amphotericin

B Arch Ophthalmol 1993 111 1326ndash7

172 Zarbin MA Becker E Witcher J et al Treatment of presumed

fungal endophthalmitis with oral fluconazole Ophthalmic Surg Lasers

1996 27 628ndash31

173 WongVK TasmanWEagleRC et al BilateralCandida parapsilo-

sis endophthalmitis Arch Ophthalmol 1997 115 670ndash2

174 Kauffman CA Bradley SF Vine AK Candida endophthalmitis

associated with intraocular lens implantation efficacy of fluconazole ther-

apy Mycoses 1993 36 13ndash17

175 del Palacio A Cuetara MS Ferro M et al Fluconazole in the man-

agement of endophthalmitis in disseminated candidosis of heroin addicts

Mycoses 1993 36 193ndash9

176 Luttrull JK Wan WL Kubak BM et al Treatment of ocular fungal

infections with oral fluconazole Am J Ophthalmol 1995 119 477ndash81

177 Akler ME Vellend H McNeely DM et al Use of fluconazole in the

treatment of candidal endophthalmitis Clin Infect Dis 1995 20 657ndash64

178 Christmas NJ Smiddy WE Vitrectomy and systemic fluconazole

for treatment of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1996 27 1012ndash18

179 EssmanTFFlynnHWSmiddyWEet al Treatment outcomes in a

10-year study of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1997 28 185ndash94

180 Martinez-Vazquez C Fernandez-Ulloa J Bordon J et al Candida

albicans endophthalmitis in brown heroin addicts response to early vit-

rectomyprecededand followedbyantifungal therapyClin InfectDis1998

27 1130ndash3

181 Aleixo MJ Caldeira L Ferreira ML Candida albicans meningitis

clinical case J Infect 2000 40 191ndash2

182 InoueY YozuR Ueda T et al A case report ofCandida parapsilo-

sis endocarditis J Heart Valve Dis 1998 7 240ndash2

183 Isalska BJ Stanbridge TN Fluconazole in the treatment of candi-

dal prosthetic valve endocarditis BMJ 1988 297 178ndash9

184 Martino P Meloni G Cassone A Candidal endocarditis and treat-

ment with fluconazole and granulocyte-macrophage colony-stimulating

factor Ann Intern Med 1990 112 966ndash7

185 Roupie E Darmon JY Brochard L et al Fluconazole therapy of

candidal native valveendocarditisEur JClinMicrobiol InfectDis199110458ndash9

186 Hernandez JA Gonzalez-Moreno M Llibre JM et al Candidal

mitral endocarditis and long-term treatment with fluconazole in a patient

with human immunodeficiency virus infection Clin Infect Dis 1992 151062ndash3

187 Venditti MDeBernardis FMicozzi A et al Fluconazole treatment

of catheter-related right-sided endocarditis caused by Candida albicans

and associated with endophthalmitis and folliculitis Clin Infect Dis 1992

14 422ndash6

188 Wallbridge DR McCartney AC Richardson MD Fluconazole in

the treatment ofCandidaprosthetic valveendocarditisMycoses199336259ndash61

189 Otaki M Kitamura N Candida prosthetic valve endocarditis An

autopsy review Int Surg 1993 78 252ndash3

190 Czwerwiec FS Bilsker MS Kamerman ML et al Long-term sur-

vival after fluconazole therapy of candidal prosthetic valve endocarditis

Am J Med 1993 94 545ndash6

191 Thakur RK Skelcy KM Kahn RN et al Successful treatment of

Candida prosthetic valve endocarditis with a combination of fluconazole

and amphotericin B Crit Care Med 1994 22 712ndash14

192 Cancelas JA Lopez JCabezudoE et al Native valve endocarditis

due toCandida parapsilosis a late complication after bonemarrow trans-

plantation-related fungemia Bone Marrow Transplant 1994 13 333ndash4

193 Zahid MA Klotz SA Hinthorn DR Medical treatment of recurrent

candidemia in a patient with probable Candida parapsilosis prosthetic

valve endocarditis Chest 1994 105 1597ndash8

194 Wells CJ Leech G Lever AM et al Treatment of native valve

Candida endocarditis with fluconazole J Infect 1995 31 233ndash5

195 Gilbert HM Peters ED Lang SJ et al Successful treatment of

fungal prosthetic valve endocarditis case report and review Clin Infect

Dis 1996 22 348ndash54

196 Nguyen MH Nguyen ML Yu VL et al Candida prosthetic valve

endocarditis prospective study of six cases and review of the literature

Clin Infect Dis 1996 22 262ndash7

197 Lejko-Zupanc T Kozelj M A case of recurrent Candida parapsilo-

sis prosthetic valve endocarditis cure bymedical treatment alone J Infect

1997 35 81ndash2

198 Joly V BelmatougN Leperre A et al Pacemaker endocarditis due

to Candida albicans case report and review Clin Infect Dis 1997 251359ndash62

199 Rex JH Walsh T Sobel JD et al Practice guidelines for the treat-

mentof candidiasis InfectiousDiseasesSocietyofAmericaClin InfectDis

2000 30 662ndash78

200 Baddour LM Long-term suppressive therapy for Candida para-

psilosis-induced prosthetic valve endocarditis Mayo Clin Proc 1995

70 773ndash5

201 Melgar GR Nasser RM Gordon SM Fungal prosthetic valve

endocarditis in 16 patients An 11-year experience in a tertiary care hos-

pital Medicine 1997 76 94ndash103

202 Dupont H Paugam-Burtz C Muller-Serieys C et al Predictive

factors of mortality due to polymicrobial peritonitis with Candida isolation

in peritoneal fluid in critically ill patients Arch Surg 2002 137 1341ndash6

203 Lee SC FungCP ChenHY et alCandida peritonitis due to peptic

ulcer perforation incidence rate risk factors prognosis and susceptibility

to fluconazole and amphotericin B Diagn Microbiol Infect Dis 2002 4423ndash7

204 Levine J Bernard DB Idelson BA et al Fungal peritonitis compli-

cating continuous ambulatory peritoneal dialysis successful treatment

with fluconazole a new orally active antifungal agent Am J Med 1989

86 825ndash7

205 Michel C Courdavault L al Khayat R et al Fungal peritonitis in

patients on peritoneal dialysis Am J Nephrol 1994 14 113ndash20

206 WangAYYuAWLi PKet al Factors predicting outcomeof fungal

peritonitis in peritoneal dialysis analysis of a 9-year experience of fungal

peritonitis in a single center Am J Kidney Dis 2000 36 1183ndash92

207 Hawkins JL Baddour LM Candida lusitaniae infections in the era

of fluconazole availability Clin Infect Dis 2003 36 14ndash18

Review

409

208 KauffmanCAVazquezJASobel JDetal Prospectivemulticenter

surveillance study of funguria in hospitalized patients The National Insti-

tute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group

Clin Infect Dis 2000 30 14ndash18

209 Sobel JD Kauffman CA McKinsey D et al Candiduria a random-

ized double-blind study of treatment with fluconazole and placebo The

National Institute of Allergy and Infectious Diseases (NIAID) Mycoses

Study Group Clin Infect Dis 2000 30 19ndash24

210 LundstromTSobel JNosocomial candiduria a reviewClin Infect

Dis 2001 32 1602ndash7

211 Kaufman D Boyle R Hazen KC et al Fluconazole prophylaxis

against fungal colonization and infection in preterm infants N Engl J

Med 2001 345 1660ndash6

212 Kicklighter SD Springer SC Cox T et al Fluconazole for the pro-

phylaxis against candidal rectal colonization in the very low birth weight

infant Pediatrics 2001 107 293ndash8

213 McGuire W Clerihew L Austin N Prophylactic intravenous anti-

fungal agents to prevent mortality and morbidity in very low birth weight

infants Cochrane Database Syst Rev 2004 CD003850

214 Agarwal JBansalSMalikGKetal Trends inneonatal septicemia

emergence of non-albicans Candida Indian Pediatr 2004 41 712ndash15

215 FasanoCOrsquoKeefe JGibbsD Fluconazole treatment of neonates

and infants with severe fungal infections not treatable with conventional

agents Eur J Clin Microbiol Infect Dis 1994 13 351ndash4

216 Wainer S Cooper PA Gouws H et al Prospective study of flu-

conazole therapy in systemicneonatal fungal infectionPediatr InfectDis J

1997 16 763ndash7

217 Huang YC Lin TY Lien RI et al Fluconazole therapy in neonatal

candidemia Am J Perinatol 2000 17 411ndash15

218 Huttova M Hartmanova I Kralinsky K et al Candida fungemia in

neonates treated with fluconazole report of forty cases including eight

with meningitis Pediatr Infect Dis J 1998 17 1012ndash15

219 Gurpinar AN Balkan E Kilic N et al Fluconazole treatment of

neonates and infants with severe fungal infections J Int Med Res 1997

25 214ndash18

220 Driessen M Ellis JB Muwazi F et al The treatment of systemic

candidiasis in neonates with oral fluconazole Ann Trop Pediatr 1997 17263ndash71

221 Driessen M Ellis JB Cooper PA et al Fluconazole vs

amphotericin B for the treatment of neonatal fungal septicemia

a prospective randomized trial Pediatr Infect Dis J 1997 151107ndash12

222 Marr B Gross S Cunningham C et al Candidal sepsis and

meningitis in a very-low-birth-weight infant successfully treated with flu-

conazole and flucytosine Clin Infect Dis 1994 19 795ndash6

223 Oleinik EM Della-Latta P Rinaldi MG et al Candida lusitaniae

osteomyelitis in a premature infant Am J Perinatol 1993 10 313ndash15

224 Mondal RK Singhi SC Chakrabarti A Randomized comparison

between fluconazole and itraconazole for the treatment of candidemia in a

pediatric intensive care unit a preliminary study Pediatr Crit Care Med

2004 5 561ndash5

225 Viscoli C Castagnola E Fioredda F et al Fluconazole in the treat-

ment of candidiasis in immunocompromised children Antimicrob Agents

Chemother 1991 35 365ndash7

226 Decruyenaere J Colardyn F Vogelaers D et al Combined use of

fluconazole and selective digestive decontamination in the prevention of

fungal infection after adult liver transplantation Transplant Proc 1995 273515ndash16

227 Koh LP Kurup A Goh YT et al Randomized trial of fluconazole

versus low-dose amphotericin B in prophylaxis against fungal infections in

patients undergoing hematopoietic stem cell transplantationAmJHema-

tol 2002 71 260ndash7

228 Gluckman E Esperou-Bourdeau H Ribaud P et al Comparaison

entre le fluconazole et le ketoconazole pour la prophylaxie des infections

fongiques chez les patients traites par greffe de moelle allogenique Cah

Oncol 1993 2 167ndash9

Review

410

48 Castaldo P Stratta RJ Wood RP et al Clinical spectrum of fungal

infections after orthotopic liver transplantation Arch Surg 1991 126149ndash56

49 Husain S Tollemar J Dominguez EA et al Changes in the spec-

trum and risk factors for invasive candidiasis in liver transplant recipients

prospective multicenter case-controlled study Transplantation 2003

75 2023ndash9

50 GeorgeMJ Snydman DRWerner BG et al The independent role

of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic

liver transplant recipients Boston Center for Liver Transplantation

CMVIG-Study Group Cytogam MedImmune Inc Gaithersburg Mary-

land Am J Med 1997 103 106ndash13

51 Dockrell DH Mendez JC Jones M et al Human herpesvirus 6

seronegativity before transplantation predicts the occurrence of fungal

infection in liver transplant recipientsTransplantation 1999 67 399ndash403

52 Tollemar J Ericzon BG Barkholt L et al Risk factors for deep

Candida infections in liver transplant recipients Transplant Proc 1990

22 1826ndash7

53 Lumbreras C Cuervas-Mons V Jara P et al Randomized trial of

fluconazole versus nystatin for the prophylaxis of Candida infection

following liver transplantation J Infect Dis 1996 174 583ndash8

54 Winston DJ Busuttil RW Randomized controlled trial of oral itra-

conazole solution versus intravenousoral fluconazole for prevention of

fungal infections in liver transplant recipients Transplantation 2002

74 688ndash95

55 Tortorano AM Viviani MA PaganoA et al Candida colonization in

orthotopic liver tranplantation fuconazole versus oral amphoericin B

J Mycol Med 1995 5 21ndash4

56 Kung N Fisher N Gunson B et al Fluconazole prophylaxis for

high-risk liver transplant recipients Lancet 1995 345 1234ndash5

57 Pappas PG Rex JH Sobel JD et al Guidelines for treatment of

candidiasis Clin Infect Dis 2004 38 161ndash89

58 PayaCV Prevention of fungal infection in transplantation TransplInfect Dis 2002 4 S46ndash51

59 LortholaryO Dupont B Antifungal prophylaxis during neutropenia

and immunodeficiency Clin Microbiol Rev 1997 10 477ndash504

60 Benedetti E Gruessner AC Troppmann C et al Intra-abdominal

fungal infections after pancreatic transplantation incidence treatment

and outcome J Am Coll Surg 1996 183 307ndash16

61 LumbrerasC Fernandez I Velosa J et al Infectious complications

following pancreatic transplantation incidence microbiological and clini-

cal characteristics and outcome Clin Infect Dis 1995 20 514ndash20

62 Patterson JE Epidemiology of fungal infections in solid organ

transplant patients Transpl Infect Dis 1999 1 229ndash36

63 Kusne S Furukawa H Abu-Elmagd K et al Infectious complica-

tions after small bowel transplantation in adults an update Transplant

Proc 1996 28 2761ndash2

64 Paterson DL Ndirangu M Kwak EJ et al Opportunistic infections

in solid-organ transplant recipients pre-treated with alumetuzumab In

Abstracts of the Forty-Fourth Interscience Conference on Antimicrobial

Agents and Chemotherapy Washington DC 2004 Abstract K-1427 p

357 American Society for Microbiology Washington DC USA

65 Kramer MR Marshall SE Starnes VA et al Infectious complica-

tions in heart-lung transplantation Analysis of 200 episodes Arch Intern

Med 1993 153 2010ndash6

66 Goodrich JMReedECMori M et al Clinical features and analysis

of risk factors for invasive candidal infection after marrow transplantation

J Infect Dis 1991 164 731ndash40

67 Dykewicz CA Centers for Disease Control and Prevention (US)

Infectious Diseases Society of America American Society of Blood and

MarrowTransplantation Summary of the guidelines for preventing oppor-

tunistic infections among hematopoietic stem cell transplant recipients

Clin Infect Dis 2001 33 139ndash44

68 Sable CA Donowitz GR Infections in bone marrow transplant

recipients Clin Infect Dis 1994 18 273ndash81

69 Goodman JLWinston DJ Greenfield RA et al A controlled trial of

fluconazole to prevent fungal infections in patients undergoing bone mar-

row transplantation N Engl J Med 1992 326 845ndash51

70 Slavin MA Osborne B Adams R et al Efficacy and safety of flu-

conazole prophylaxis for fungal infectionsaftermarrow transplantationmdasha

prospective randomized double-blind study J Infect Dis 1995 1711545ndash52

71 Marr KA Seidel K SlavinMA et al Prolonged fluconazole prophy-

laxis is associated with persistent protection against candidiasis-related

death in allogeneic marrow transplant recipients long-term follow-up of a

randomized placebo-controlled trial Blood 2000 96 2055ndash61

72 AlangadenGChandrasekar PH BaileyE et al Antifungal prophy-

laxis with low-dose fluconazole during bone marrow transplantation The

Bone Marrow Transplantation Team Bone Marrow Transplant 1994 14919ndash24

73 Wolff SN Fay J Stevens D et al Fluconazole versus low-dose

amphotericin B for the prevention of fungal infections in patients under-

going bonemarrow transplantation a study of theNorthAmericanMarrow

Transplant Group Bone Marrow Transplant 2000 25 853ndash9

74 Annaloro C Oriana A Tagliaferri E et al Efficacy of different pro-

phylactic antifungal regimens in bone marrow transplantation Haemato-

logica 1995 80 512ndash17

75 Winston DJ Maziarz RT Chandrasekar PH et al Intravenous and

oral itraconazole versus intravenous and oral fluconazole for long-term

antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant

recipients A multicenter randomized trial Ann Intern Med 2003 138705ndash13

76 MarrKACrippaF LeisenringWet al Itraconazoleversus flucona-

zole forpreventionof fungal infections inpatients receivingallogeneicstem

cell transplants Blood 2004 103 1527ndash33

77 MacMillan ML Goodman JL DeFor TE et al Fluconazole to pre-

vent yeast infections in bone marrow transplantation patients a random-

ized trial of high versus reduced dose and determination of the value of

maintenance therapy Am J Med 2002 112 369ndash79

78 Marr KA Seidel K White TC et al Candidemia in allogeneic blood

and marrow transplant recipients evolution of risk factors after the adop-

tion of prophylactic fluconazole J Infect Dis 2000 181 309ndash16

79 van Burik JA Ratanatharathorn V Stepan DE et al Micafungin

versus fluconazole for prophylaxis against invasive fungal infections dur-

ing neutropenia in patients undergoing hematopoietic stem cell trans-

plantation Clin Infect Dis 2004 39 1407ndash16

80 Prentice HG Kibbler CC Prentice AG Towards a targeted risk-

based antifungal strategy in neutropenic patients Br J Haematol 2000

110 273ndash84

81 Laverdiere M Rotstein C Bow EJ et al Impact of fluconazole

prophylaxis on fungal colonizatin and infection rates in neutropenic

patients The Canadian Fluconazole Study J Animicrob Chemother

2000 46 1001ndash8

82 Winston DJ Chandrasekar PH Lazarus HM et al Fluconazole

prophylaxis of fungal infections in patients with acute leukemia Results

of a randomized placebo-controlled double-blind multicenter trial Ann

Intern Med 1993 118 495ndash503

83 Chandrasekar PHGatnyCMEffect of fluconazole prophylaxis on

fever and use of amphotericin in neutropenic cancer patients Bone Mar-

row Transplantation Team Chemotherapy 1994 40 136ndash43

84 Rotstein C Bow EJ Laverdiere M et al Randomized placebo-

controlled trial of fluconazole prophylaxis for neutropenic cancer patients

benefit basedonpurposeand intensity of cytotoxic therapy TheCanadian

Fluconazole Prophylaxis Study Group Clin Infect Dis 1999 28 331ndash40

85 YamacK Senol E HaznedarR Prophylactic use of fluconazole in

neutropenic cancer patients Postgrad Med J 1997 71 284ndash6

86 KernW BehreG Rudolf T et al Failure of fluconazole prophylaxis

to reducemortality or the requirement of systemic amphotericin B therapy

during treatment for refractory acute myeloid leukemia results of a

Review

406

prospective randomized phase III study German AML Cooperative

Group Cancer 1998 83 291ndash301

87 SchaffnerA SchaffnerM Effect of prophylactic fluconazole on the

frequencyof fungal infectionsamphotericinBuseandhealthcarecosts in

patients undergoing intensive chemotherapy for hematologic neoplasias

J Infect Dis 1995 172 1035ndash41

88 Egger T Gratwohl A Tichelli A et al Comparison of fluconazole

with oral polyenes in the prevention of fungal infections in neutropenic

patients A prospective randomized single-center study Support Care

Cancer 1995 3 139ndash46

89 Morgenstern GR Prentice AG Prentice H et al A randomized

controlled trial of itraconazole versus fluconazole for the prevention of

fungal infections in patients with haematological malignancies UK Mul-

ticentre Antifungal Prophylaxis Study Group Br J Haematol 1999 105901ndash11

90 EllisMEClinkHErnstPetalControlledstudyof fluconazole in the

preventionof fungal infections in neutropenic patientswith haematological

malignancies and bone marrow transplant recipients Eur J Clin Microbiol

Infect Dis 1994 13 3ndash11

91 Philpott-Howard JN Wade JJ Mufti GJ et al Randomized com-

parisonoforal fluconazoleversusoralpolyenes for thepreventionof fungal

infection in patients at risk of neutropenia Multicentre Study Group

J Antimicrob Chemother 1993 31 973ndash84

92 Ninane J A multicentre study of fluconazole versus oral polyenes

in the prevention of fungal infection in children with hematological or

oncological malignancies Multicentre Study Group Eur J Clin Microbiol

Infect Dis 1994 13 330ndash7

93 Menichetti F Del Favero A Martino P et al Preventing fungal

infection in neutropenic patients with acute leukemia fluconazole com-

pared with oral amphotericin B The GIMEMA Infection Program Ann

Intern Med 1994 120 913ndash18

94 Akiyama H Mori S Tanikawa S et al Fluconazole versus oral

amphotericin B in preventing fungal infection in chemotherapy-induced

neutropenic patients with haematological malignancies Mycoses 1996

36 373ndash8

95 Meunier F AounM JanssensM et al Chemoprophylaxis of fungal

infections in granulocytopenic patients using fluconazole versus oral

amphotericin B Drug Invest 1991 3 258ndash65

96 Rozenberg-Arska M Dekker AW Branger J et al A randomized

study to compare oral fluconazole to amphotericin B in the prevention of

fungal infections inpatientswithacute leukaemiaJAntimicrobChemother

1991 27 369ndash76

97 Brammer KW Management of fungal infection in neutropenic

patients with fluconazole Haematol Blood Transfus 1990 33 546ndash50

98 Bodey GP Anaissie EJ Elting LS et al Antifungal prophylaxis

during remission induction therapy for acute leukemia fluconazole versus

intravenous amphotericin B Cancer 1994 73 2099ndash106

99 Kanda Y Yamamoto R Chizuka A et al Prophylactic action of

oral fluconazole against fungal infection in neutropenic patients A

meta-analysis of 16 randomized controlled trials Cancer 2000 891611ndash25

100 Bow EJ Laverdiere M Lussier N et al Antifungal prophylaxis for

severely neutropenic chemotherapy recipients a meta analysis of

randomized-controlled clinical trials Cancer 2002 94 3230ndash46

101 Viscoli C Paesmans M Sanz M et al Association between

antifungal prophylaxis and rate of documented bacteremia in febrile

neutropenic cancer patients Clin Infect Dis 2001 32 1532ndash7

102 HughesWT Armstrong D BodeyGP et al 2002 guidelines for the

use of antimicrobial agents in neutropenic patients with cancerClin Infect

Dis 2002 34 730ndash51

103 Cornely OA Bohme A Buchheidt D et al Prophylaxis of invasive

fungal infections in patients with hematological malignancies and solid

tumorsmdashguidelines of the Infectious Diseases Working Party (AGIHO)

of the German Society of Hematology and Oncology (DGHO) Ann

Hematol 2003 82 Suppl 2 186ndash200

104 McNeil MM Nash SL Hajjeh RA et al Trends in mortality due to

invasivemycotic diseases in theUnitedStates 1980ndash1997Clin InfectDis

2001 33 641ndash7

105 KibblerCCSeatonSBarnesRA et alManagement and outcome

of bloodstream infections due to Candida species in England and Wales

J Hosp Infect 2003 54 18ndash24

106 Marchetti O Bille J Fluckiger U et al Fungal Infection Network of

Switzerland Epidemiology of candidemia in Swiss tertiary care hospitals

secular trends 1991-2000 Clin Infect Dis 2004 38 311ndash20

107 Gudlaugsson O Gillespie S Lee K et al Attributable mortality of

nosocomial candidemia revisited Clin Infect Dis 2003 37 1172ndash7

108 Ibanez-Nolla J Nolla-Salas M Leon MA et al Early diagnosis of

candidiasis in nonneutropenic critically ill patients J Infect 2004 48181ndash92

109 BlumbergHMJarvisWRSoucieJMetalRisk factors for candidal

bloodstream infections in surgical intensive care unit patients the NEMIS

prospective multicenter study The National Epidemiology of Mycosis

Survey Clin Infect Dis 2001 33 177ndash86

110 Pittet D Monod M Suter PM et al Candida colonization and

subsequent infections in critically ill surgical patients Ann Surg 1994

220 751ndash8

111 Sendid B Poirot JL Tabouret M et al Combined detection of

mannanaemia and antimannan antibodies as a strategy for the diagnosis

of systemic infectioncausedbypathogenicCandidaspeciesJMedMicro-

biol 2002 51 433ndash42

112 Bar W Hecker H Diagnosis of systemic Candida infections in

patients of the intensive care unit Significance of serum antigens and

antibodies Mycoses 2002 45 22ndash8

113 Calandra T Marchetti O Clinical trials of antifungal prophy-

laxis among patients undergoing surgery Clin Infect Dis 2004 39S185ndash92

114 Sypula WT Kale-Pradhan PB Therapeutic dilemma of flucona-

zole prophylaxis in intensive care Ann Pharmacother 2002 36 155ndash9

115 Pelz RK Hendrix CW Swoboda SM et al Double-blind placebo-

controlled trial of fluconazole to prevent candidal infections in critically ill

surgical patients Ann Surg 2001 233 542ndash8

116 Eggimann P Francioli P Bille J et al Fluconazole prophylaxis

prevents intraabdominal candidiasis in high-risk surgical patients Crit

Care Med 1997 27 1066ndash72

117 Swoboda SM Merz WG Lipsetta PA Candidemia the impact of

antifungal prophylaxis in a surgical intensive care unitSurg Infect20034345ndash54

118 Todd JC OrsquoNeal VG Grady KP et al Reduction of secondary

mycotic infections in the trauma intensivie care unit with fluconazole

J Trauma 1991 31 1722ndash27

119 Jacobs S Price Evans DA Tariq M et al Fluconazole improves

survival in septic shock a randomized double-blind prospective studyCrit

Care Med 2003 31 1938ndash46

120 Zervos EE Fink GW Norman JG et al Fluconazole increases

bactericidal activity of neutrophils through non-cytokine-mediated path-

way J Trauma 1996 41 465ndash70

121 AblesAZBlumerNAValainisGTetal Fluconazoleprophylaxis of

severe Candida infection in trauma and postsurgical patients a prospec-

tive double-blind randomised placebo-controlled trial Infect Dis Clin

Pract 2000 9 169ndash75

122 Kam LW Lin JD Management of systemic candidal infections in

the intensive care unit Am J Health Syst Pharm 2002 59 33ndash41

123 Rocco TR Reinert SE Simms HH Effects of fluconazole admin-

istration in critically ill patients analysis of bacterial and fungal resistance

Arch Surg 2000 135 160ndash5

124 Tortorano AM Caspani L Rigoni AL et al Candidosis in the inten-

sive care unit a 20-year survey J Hosp Infect 2004 57 8ndash13

125 EggimannPGarbino J Pittet DManagement ofCandida species

infections in critically ill patients Lancet Infect Dis 2003 3 772ndash85

Review

407

126 EggimannPGarbinoJPittetDEpidemiologyofCandida species

infections incritically ill non-immunosuppressedpatientsLancet InfectDis

2003 3 685ndash702

127 Martins MD Lozano-Chiu M Rex JH Declining rates of oropha-

ryngeal candidiasis and carriage of Candida albicans associated with

trends toward reduced rates of carriage of fluconazole-resistant C albi-

cans in human immunodeficiency virus-infected patients Clin Infect Dis

1998 27 1291ndash4

128 Powderly WG Finkelstein D Feinberg J et al A randomized trial

comparing fluconazole with clotrimazole troches for the prevention of fun-

gal infections in patients with advanced human immunodeficiency virus

infection NIAID AIDS Clinical Trials Group N Engl J Med 1995 332700ndash5

129 Leen CL Dunbar EM Ellis ME et al Once-weekly fluconazole to

prevent recurrenceof oropharyngeal candidiasis inpatientswithAIDSand

AIDS-related complex a double-blind placebo-controlled study J Infect

1990 21 55ndash60

130 Stevens DA Greene SI Lang OS Thrush can be prevented in

patients with acquired immunodeficiency syndrome and the acquired

immunodeficiency syndrome-related complex Randomized double-

blind placebo-controlled study of 100-mg oral fluconazole daily Arch

Intern Med 1991 151 2458ndash64

131 Just-Nubling G Gentschew G Meissner K Fluconazole prophy-

laxis of recurrent oral candidiasis inHIV-positive patientsEur JClinMicro-

biol Infect Dis 1991 10 917ndash21

132 Marriott DJ Jones PD Hoy JF et al Fluconazole once a week as

secondary prophylaxis against oropharyngeal candidiasis in HIV-infected

patients A double-blind placebo-controlled studyMed J Aust 1993 158312ndash16

133 Schuman P Capps L Peng G et al Weekly fluconazole for the

prevention ofmucosal candidiasis inwomenwithHIV infection A random-

ized double-blind placebo-controlled trial Terry Beirn Community Pro-

grams for Clinical Research on AIDSAnn InternMed 1997 126 689ndash96

134 Havlir DV DubeMPMcCutchan JA et al Prophylaxis with weekly

versus daily fluconazole for fungal infections in patients with AIDS Clin

Infect Dis 1998 27 1369ndash75

135 Pagani JL Chave JP Casjka C et al Efficacy tolerability and

development of resistance in HIV-positive patients treated with flucona-

zole for secondary prevention of oropharyngeal candidiasis a random-

ized double-blind placebo-controlled trial JAntimicrobChemother 2002

50 231ndash40

136 Vazquez JA Peng G Sobel JD et al Evolution of antifungal sus-

ceptibility amongCandidaspecies isolates recovered fromhuman immun-

odeficiency virus-infected women receiving fluconazole prophylaxis Clin

Infect Dis 2001 33 1069ndash75

137 Delfraissy JF Prise en charge therapeutique des patients infectespas le VIH Rapport Delfraissy Paris Flammarion 2004

138 DePauwBERaemaekers JMDonnelly JPet al Anopenstudyon

the safety and efficacy of fluconazole in the treatment of disseminated

Candida infections in patients treated for hematological malignancy Ann

Hematol 1995 70 83ndash7

139 Anaissie EJ Vartivarian SE Abi-Said D et al Fluconazole versus

amphotericin B in the treatment of hematogenous candidiasis a matched

cohort study Am J Med 1996 101 170ndash6

140 Anaissie EJ Darouiche RO Abi-Said D et al Management of

invasive candidal infections results of a prospective randomized multi-

center study of fluconazole versus amphotericin B and review of the

literature Clin Infect Dis 1996 23 964ndash72

141 Myoken Y Kyo T Kohara T et al Breakthrough fungemia caused

by azole-resistant Candida albicans in neutropenic patients with acute

leukemia Clin Infect Dis 2003 36 1496ndash7

142 Anttila VJ FarkkilaM JanssonSE et al Diagnostic laparoscopy in

patientswith acute leukemiaandsuspectedhepatic candidiasisEur JClin

Microbiol Infect Dis 1997 16 637ndash43

143 Anaissie E Bodey GP Kantarjian H et al Fluconazole therapy for

chronic disseminated candidiasis in patients with leukemia and prior

amphotericin B therapy Am J Med 1991 91 142ndash50

144 KauffmanCA BradleySFRossSC et al Hepatosplenic candidia-

sis successful treatment with fluconazole Am J Med 1991 91 137ndash41

145 Kontoyiannis DP Luna MA Samuels BI et al Hepatosplenic can-

didiasis A manifestation of chronic disseminated candidiasis Infect Dis

Clin North Am 2000 14 721ndash39

146 Graninger W Presteril E Schneeweiss B et al Treatment of

Candida albicans fungaemia with fluconazole J Infect 1993 26 133ndash46

147 Phillips P Shafran S Garber G et al Multicenter randomized trial

of fluconazole versus amphotericin B for treatment of candidemia in

non-neutropenic patients Canadian Candidemia Study Group Eur J

Clin Microbiol Infect Dis 1997 16 337ndash45

148 Rex JH Bennett JE Sugar AM et alA randomized trial comparing

fluconazolewithamphotericinB for the treatmentof candidemia inpatients

without neutropenia Candidemia Study Group and the National Institute

N Engl J Med 1994 331 1325ndash30

149 Abele-Horn M Kopp A Sternberg U et al A randomized study

comparing fluconazolewith amphotericinB5-flucytosine for the treatment

of systemic Candida infections in intensive care patients Infection 1996

24 426ndash32

150 Nguyen MH Peacock JE Jr Tanner DC et al Therapeutic

approaches in patients with candidemia Evaluation in a multicenter

prospective observational study Arch Intern Med 1995 155 2429ndash35

151 Rex JH Pappas PG Karchmer AW et al A randomized and

blinded multicenter trial of high-dose fluconazole plus placebo versus flu-

conazole plus amphotericin B as therapy for candidemia and its con-

sequences in non-neutropenic subjectsClin Infect Dis 2003 36 1221ndash8

152 Mora-Duarte J Betts R Rotstein C et al Comparison of

caspofungin and amphotericin B for invasive candidiasis N Engl J Med

2002 347 2020ndash9

153 Sugar AM Saunders C Diamond RD et al Successful treatment

of Candida osteomyelitis with fluconazole A noncomparative study of

two patients Diagn Microbiol Infect Dis 1990 13 517ndash20

154 Tang C Successful treatment of Candida albicans osteomyelitis

with fluconazole J Infect 1993 26 89ndash92

155 LafontAOliveAGelmanMet alCandidaalbicansspondylodisci-

tis and vertebral osteomyelitis in patients with intravenous heroin drug

addiction Report of 3 new cases J Rheumatol 1994 21 953ndash6

156 Hennequin C Bouree P Hiesse C et al Spondylodiskitis due to

Candida albicans report of two patients who were successfully treated

with fluconazole and review of the literature Clin Infect Dis 1996 23176ndash8

157 Jonnalagadda S VeerabaguMP Rakela J et alCandida albicans

osteomyelitis in a liver transplant recipient a case report and review of the

literature Transplantation 1996 62 1182ndash4

158 Rossel P Schonheyder HC Nielsen H Fluconazole therapy

inCandidaalbicansspondylodiscitisScandJ InfectDis199830 527ndash30

159 TurnerDLJohnsonSARuleSASuccessful treatmentof candidal

osteomyelitis with fluconazole following failure with liposomal ampho-

tericin B J Infect 1999 38 51ndash3

160 El-Zaatari MM Hulten K Fares Y et al Successful treatment of

Candida albicans osteomyelitis of the spine with fluconazole and surgical

debridement case report J Chemother 2002 14 627ndash30

161 Seravalli L Van Linthoudt D Bernet C et al Candida glabrata

spinal osteomyelitis involving two contiguous lumbar vertebrae a case

report and review of the literature Diagn Microbiol Infect Dis 2003 45137ndash41

162 Garbino J Schnyder I LewDP et al An unusual cause of vertebral

osteomyelitis Candida species Scand J Infect Dis 2003 35 288ndash91

163 TunkelARThomasCYWispelweyBCandidaprostheticarthritis

report of a case treated with fluconazole and review of the literature Am J

Med 1993 94 100ndash3

Review

408

164 CushingRD FulgenziWR Synovial fluid levels of fluconazole in a

patient with Candida parapsilosis prosthetic joint infection who had an

excellent clinical response J Arthroplasty 1997 12 950

165 Fukasawa N Shirakura K Candida arthritis after total knee

arthroplastymdasha case of successful treatment without prosthesis removal

Acta Orthop Scand 1997 68 306ndash7

166 Lerch K Kalteis T Schubert T et al Prosthetic joint infections with

osteomyelitis due to Candida albicans Mycoses 2003 46 462ndash6

167 Clancy CJ Nguyen MH Morris AJ Candidal mediastinitis an

emerging clinical entity Clin Infect Dis 1997 25 608ndash13

168 PetrikkosGSkiadaA SabatakouH et al Case report Successful

treatment of two cases of post-surgical sternal osteomyelitis due to

Candida krusei and Candida albicans respectively with high doses of

triazoles (fluconazole itraconazole) Mycoses 2001 44 422ndash5

169 Weers-Pothoff GHavermans JF Kamphuis J et alCandida tropi-

calis arthritis in a patient with acutemyeloid leukemia successfully treated

with fluconazole case report and review of the literature Infection 1997

25 109ndash11

170 Laatikainen L TuominenM vonDickhoff K Treatment of endoge-

nous fungal endophthalmitis with systemic fluconazole with or without

vitrectomy Am J Ophthalmol 1992 113 205ndash7

171 Borne MJ Elliott JH OrsquoDay DM Ocular fluconazole treatment of

Candidaparapsilosisendophthalmitis after failed intravitreal amphotericin

B Arch Ophthalmol 1993 111 1326ndash7

172 Zarbin MA Becker E Witcher J et al Treatment of presumed

fungal endophthalmitis with oral fluconazole Ophthalmic Surg Lasers

1996 27 628ndash31

173 WongVK TasmanWEagleRC et al BilateralCandida parapsilo-

sis endophthalmitis Arch Ophthalmol 1997 115 670ndash2

174 Kauffman CA Bradley SF Vine AK Candida endophthalmitis

associated with intraocular lens implantation efficacy of fluconazole ther-

apy Mycoses 1993 36 13ndash17

175 del Palacio A Cuetara MS Ferro M et al Fluconazole in the man-

agement of endophthalmitis in disseminated candidosis of heroin addicts

Mycoses 1993 36 193ndash9

176 Luttrull JK Wan WL Kubak BM et al Treatment of ocular fungal

infections with oral fluconazole Am J Ophthalmol 1995 119 477ndash81

177 Akler ME Vellend H McNeely DM et al Use of fluconazole in the

treatment of candidal endophthalmitis Clin Infect Dis 1995 20 657ndash64

178 Christmas NJ Smiddy WE Vitrectomy and systemic fluconazole

for treatment of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1996 27 1012ndash18

179 EssmanTFFlynnHWSmiddyWEet al Treatment outcomes in a

10-year study of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1997 28 185ndash94

180 Martinez-Vazquez C Fernandez-Ulloa J Bordon J et al Candida

albicans endophthalmitis in brown heroin addicts response to early vit-

rectomyprecededand followedbyantifungal therapyClin InfectDis1998

27 1130ndash3

181 Aleixo MJ Caldeira L Ferreira ML Candida albicans meningitis

clinical case J Infect 2000 40 191ndash2

182 InoueY YozuR Ueda T et al A case report ofCandida parapsilo-

sis endocarditis J Heart Valve Dis 1998 7 240ndash2

183 Isalska BJ Stanbridge TN Fluconazole in the treatment of candi-

dal prosthetic valve endocarditis BMJ 1988 297 178ndash9

184 Martino P Meloni G Cassone A Candidal endocarditis and treat-

ment with fluconazole and granulocyte-macrophage colony-stimulating

factor Ann Intern Med 1990 112 966ndash7

185 Roupie E Darmon JY Brochard L et al Fluconazole therapy of

candidal native valveendocarditisEur JClinMicrobiol InfectDis199110458ndash9

186 Hernandez JA Gonzalez-Moreno M Llibre JM et al Candidal

mitral endocarditis and long-term treatment with fluconazole in a patient

with human immunodeficiency virus infection Clin Infect Dis 1992 151062ndash3

187 Venditti MDeBernardis FMicozzi A et al Fluconazole treatment

of catheter-related right-sided endocarditis caused by Candida albicans

and associated with endophthalmitis and folliculitis Clin Infect Dis 1992

14 422ndash6

188 Wallbridge DR McCartney AC Richardson MD Fluconazole in

the treatment ofCandidaprosthetic valveendocarditisMycoses199336259ndash61

189 Otaki M Kitamura N Candida prosthetic valve endocarditis An

autopsy review Int Surg 1993 78 252ndash3

190 Czwerwiec FS Bilsker MS Kamerman ML et al Long-term sur-

vival after fluconazole therapy of candidal prosthetic valve endocarditis

Am J Med 1993 94 545ndash6

191 Thakur RK Skelcy KM Kahn RN et al Successful treatment of

Candida prosthetic valve endocarditis with a combination of fluconazole

and amphotericin B Crit Care Med 1994 22 712ndash14

192 Cancelas JA Lopez JCabezudoE et al Native valve endocarditis

due toCandida parapsilosis a late complication after bonemarrow trans-

plantation-related fungemia Bone Marrow Transplant 1994 13 333ndash4

193 Zahid MA Klotz SA Hinthorn DR Medical treatment of recurrent

candidemia in a patient with probable Candida parapsilosis prosthetic

valve endocarditis Chest 1994 105 1597ndash8

194 Wells CJ Leech G Lever AM et al Treatment of native valve

Candida endocarditis with fluconazole J Infect 1995 31 233ndash5

195 Gilbert HM Peters ED Lang SJ et al Successful treatment of

fungal prosthetic valve endocarditis case report and review Clin Infect

Dis 1996 22 348ndash54

196 Nguyen MH Nguyen ML Yu VL et al Candida prosthetic valve

endocarditis prospective study of six cases and review of the literature

Clin Infect Dis 1996 22 262ndash7

197 Lejko-Zupanc T Kozelj M A case of recurrent Candida parapsilo-

sis prosthetic valve endocarditis cure bymedical treatment alone J Infect

1997 35 81ndash2

198 Joly V BelmatougN Leperre A et al Pacemaker endocarditis due

to Candida albicans case report and review Clin Infect Dis 1997 251359ndash62

199 Rex JH Walsh T Sobel JD et al Practice guidelines for the treat-

mentof candidiasis InfectiousDiseasesSocietyofAmericaClin InfectDis

2000 30 662ndash78

200 Baddour LM Long-term suppressive therapy for Candida para-

psilosis-induced prosthetic valve endocarditis Mayo Clin Proc 1995

70 773ndash5

201 Melgar GR Nasser RM Gordon SM Fungal prosthetic valve

endocarditis in 16 patients An 11-year experience in a tertiary care hos-

pital Medicine 1997 76 94ndash103

202 Dupont H Paugam-Burtz C Muller-Serieys C et al Predictive

factors of mortality due to polymicrobial peritonitis with Candida isolation

in peritoneal fluid in critically ill patients Arch Surg 2002 137 1341ndash6

203 Lee SC FungCP ChenHY et alCandida peritonitis due to peptic

ulcer perforation incidence rate risk factors prognosis and susceptibility

to fluconazole and amphotericin B Diagn Microbiol Infect Dis 2002 4423ndash7

204 Levine J Bernard DB Idelson BA et al Fungal peritonitis compli-

cating continuous ambulatory peritoneal dialysis successful treatment

with fluconazole a new orally active antifungal agent Am J Med 1989

86 825ndash7

205 Michel C Courdavault L al Khayat R et al Fungal peritonitis in

patients on peritoneal dialysis Am J Nephrol 1994 14 113ndash20

206 WangAYYuAWLi PKet al Factors predicting outcomeof fungal

peritonitis in peritoneal dialysis analysis of a 9-year experience of fungal

peritonitis in a single center Am J Kidney Dis 2000 36 1183ndash92

207 Hawkins JL Baddour LM Candida lusitaniae infections in the era

of fluconazole availability Clin Infect Dis 2003 36 14ndash18

Review

409

208 KauffmanCAVazquezJASobel JDetal Prospectivemulticenter

surveillance study of funguria in hospitalized patients The National Insti-

tute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group

Clin Infect Dis 2000 30 14ndash18

209 Sobel JD Kauffman CA McKinsey D et al Candiduria a random-

ized double-blind study of treatment with fluconazole and placebo The

National Institute of Allergy and Infectious Diseases (NIAID) Mycoses

Study Group Clin Infect Dis 2000 30 19ndash24

210 LundstromTSobel JNosocomial candiduria a reviewClin Infect

Dis 2001 32 1602ndash7

211 Kaufman D Boyle R Hazen KC et al Fluconazole prophylaxis

against fungal colonization and infection in preterm infants N Engl J

Med 2001 345 1660ndash6

212 Kicklighter SD Springer SC Cox T et al Fluconazole for the pro-

phylaxis against candidal rectal colonization in the very low birth weight

infant Pediatrics 2001 107 293ndash8

213 McGuire W Clerihew L Austin N Prophylactic intravenous anti-

fungal agents to prevent mortality and morbidity in very low birth weight

infants Cochrane Database Syst Rev 2004 CD003850

214 Agarwal JBansalSMalikGKetal Trends inneonatal septicemia

emergence of non-albicans Candida Indian Pediatr 2004 41 712ndash15

215 FasanoCOrsquoKeefe JGibbsD Fluconazole treatment of neonates

and infants with severe fungal infections not treatable with conventional

agents Eur J Clin Microbiol Infect Dis 1994 13 351ndash4

216 Wainer S Cooper PA Gouws H et al Prospective study of flu-

conazole therapy in systemicneonatal fungal infectionPediatr InfectDis J

1997 16 763ndash7

217 Huang YC Lin TY Lien RI et al Fluconazole therapy in neonatal

candidemia Am J Perinatol 2000 17 411ndash15

218 Huttova M Hartmanova I Kralinsky K et al Candida fungemia in

neonates treated with fluconazole report of forty cases including eight

with meningitis Pediatr Infect Dis J 1998 17 1012ndash15

219 Gurpinar AN Balkan E Kilic N et al Fluconazole treatment of

neonates and infants with severe fungal infections J Int Med Res 1997

25 214ndash18

220 Driessen M Ellis JB Muwazi F et al The treatment of systemic

candidiasis in neonates with oral fluconazole Ann Trop Pediatr 1997 17263ndash71

221 Driessen M Ellis JB Cooper PA et al Fluconazole vs

amphotericin B for the treatment of neonatal fungal septicemia

a prospective randomized trial Pediatr Infect Dis J 1997 151107ndash12

222 Marr B Gross S Cunningham C et al Candidal sepsis and

meningitis in a very-low-birth-weight infant successfully treated with flu-

conazole and flucytosine Clin Infect Dis 1994 19 795ndash6

223 Oleinik EM Della-Latta P Rinaldi MG et al Candida lusitaniae

osteomyelitis in a premature infant Am J Perinatol 1993 10 313ndash15

224 Mondal RK Singhi SC Chakrabarti A Randomized comparison

between fluconazole and itraconazole for the treatment of candidemia in a

pediatric intensive care unit a preliminary study Pediatr Crit Care Med

2004 5 561ndash5

225 Viscoli C Castagnola E Fioredda F et al Fluconazole in the treat-

ment of candidiasis in immunocompromised children Antimicrob Agents

Chemother 1991 35 365ndash7

226 Decruyenaere J Colardyn F Vogelaers D et al Combined use of

fluconazole and selective digestive decontamination in the prevention of

fungal infection after adult liver transplantation Transplant Proc 1995 273515ndash16

227 Koh LP Kurup A Goh YT et al Randomized trial of fluconazole

versus low-dose amphotericin B in prophylaxis against fungal infections in

patients undergoing hematopoietic stem cell transplantationAmJHema-

tol 2002 71 260ndash7

228 Gluckman E Esperou-Bourdeau H Ribaud P et al Comparaison

entre le fluconazole et le ketoconazole pour la prophylaxie des infections

fongiques chez les patients traites par greffe de moelle allogenique Cah

Oncol 1993 2 167ndash9

Review

410

prospective randomized phase III study German AML Cooperative

Group Cancer 1998 83 291ndash301

87 SchaffnerA SchaffnerM Effect of prophylactic fluconazole on the

frequencyof fungal infectionsamphotericinBuseandhealthcarecosts in

patients undergoing intensive chemotherapy for hematologic neoplasias

J Infect Dis 1995 172 1035ndash41

88 Egger T Gratwohl A Tichelli A et al Comparison of fluconazole

with oral polyenes in the prevention of fungal infections in neutropenic

patients A prospective randomized single-center study Support Care

Cancer 1995 3 139ndash46

89 Morgenstern GR Prentice AG Prentice H et al A randomized

controlled trial of itraconazole versus fluconazole for the prevention of

fungal infections in patients with haematological malignancies UK Mul-

ticentre Antifungal Prophylaxis Study Group Br J Haematol 1999 105901ndash11

90 EllisMEClinkHErnstPetalControlledstudyof fluconazole in the

preventionof fungal infections in neutropenic patientswith haematological

malignancies and bone marrow transplant recipients Eur J Clin Microbiol

Infect Dis 1994 13 3ndash11

91 Philpott-Howard JN Wade JJ Mufti GJ et al Randomized com-

parisonoforal fluconazoleversusoralpolyenes for thepreventionof fungal

infection in patients at risk of neutropenia Multicentre Study Group

J Antimicrob Chemother 1993 31 973ndash84

92 Ninane J A multicentre study of fluconazole versus oral polyenes

in the prevention of fungal infection in children with hematological or

oncological malignancies Multicentre Study Group Eur J Clin Microbiol

Infect Dis 1994 13 330ndash7

93 Menichetti F Del Favero A Martino P et al Preventing fungal

infection in neutropenic patients with acute leukemia fluconazole com-

pared with oral amphotericin B The GIMEMA Infection Program Ann

Intern Med 1994 120 913ndash18

94 Akiyama H Mori S Tanikawa S et al Fluconazole versus oral

amphotericin B in preventing fungal infection in chemotherapy-induced

neutropenic patients with haematological malignancies Mycoses 1996

36 373ndash8

95 Meunier F AounM JanssensM et al Chemoprophylaxis of fungal

infections in granulocytopenic patients using fluconazole versus oral

amphotericin B Drug Invest 1991 3 258ndash65

96 Rozenberg-Arska M Dekker AW Branger J et al A randomized

study to compare oral fluconazole to amphotericin B in the prevention of

fungal infections inpatientswithacute leukaemiaJAntimicrobChemother

1991 27 369ndash76

97 Brammer KW Management of fungal infection in neutropenic

patients with fluconazole Haematol Blood Transfus 1990 33 546ndash50

98 Bodey GP Anaissie EJ Elting LS et al Antifungal prophylaxis

during remission induction therapy for acute leukemia fluconazole versus

intravenous amphotericin B Cancer 1994 73 2099ndash106

99 Kanda Y Yamamoto R Chizuka A et al Prophylactic action of

oral fluconazole against fungal infection in neutropenic patients A

meta-analysis of 16 randomized controlled trials Cancer 2000 891611ndash25

100 Bow EJ Laverdiere M Lussier N et al Antifungal prophylaxis for

severely neutropenic chemotherapy recipients a meta analysis of

randomized-controlled clinical trials Cancer 2002 94 3230ndash46

101 Viscoli C Paesmans M Sanz M et al Association between

antifungal prophylaxis and rate of documented bacteremia in febrile

neutropenic cancer patients Clin Infect Dis 2001 32 1532ndash7

102 HughesWT Armstrong D BodeyGP et al 2002 guidelines for the

use of antimicrobial agents in neutropenic patients with cancerClin Infect

Dis 2002 34 730ndash51

103 Cornely OA Bohme A Buchheidt D et al Prophylaxis of invasive

fungal infections in patients with hematological malignancies and solid

tumorsmdashguidelines of the Infectious Diseases Working Party (AGIHO)

of the German Society of Hematology and Oncology (DGHO) Ann

Hematol 2003 82 Suppl 2 186ndash200

104 McNeil MM Nash SL Hajjeh RA et al Trends in mortality due to

invasivemycotic diseases in theUnitedStates 1980ndash1997Clin InfectDis

2001 33 641ndash7

105 KibblerCCSeatonSBarnesRA et alManagement and outcome

of bloodstream infections due to Candida species in England and Wales

J Hosp Infect 2003 54 18ndash24

106 Marchetti O Bille J Fluckiger U et al Fungal Infection Network of

Switzerland Epidemiology of candidemia in Swiss tertiary care hospitals

secular trends 1991-2000 Clin Infect Dis 2004 38 311ndash20

107 Gudlaugsson O Gillespie S Lee K et al Attributable mortality of

nosocomial candidemia revisited Clin Infect Dis 2003 37 1172ndash7

108 Ibanez-Nolla J Nolla-Salas M Leon MA et al Early diagnosis of

candidiasis in nonneutropenic critically ill patients J Infect 2004 48181ndash92

109 BlumbergHMJarvisWRSoucieJMetalRisk factors for candidal

bloodstream infections in surgical intensive care unit patients the NEMIS

prospective multicenter study The National Epidemiology of Mycosis

Survey Clin Infect Dis 2001 33 177ndash86

110 Pittet D Monod M Suter PM et al Candida colonization and

subsequent infections in critically ill surgical patients Ann Surg 1994

220 751ndash8

111 Sendid B Poirot JL Tabouret M et al Combined detection of

mannanaemia and antimannan antibodies as a strategy for the diagnosis

of systemic infectioncausedbypathogenicCandidaspeciesJMedMicro-

biol 2002 51 433ndash42

112 Bar W Hecker H Diagnosis of systemic Candida infections in

patients of the intensive care unit Significance of serum antigens and

antibodies Mycoses 2002 45 22ndash8

113 Calandra T Marchetti O Clinical trials of antifungal prophy-

laxis among patients undergoing surgery Clin Infect Dis 2004 39S185ndash92

114 Sypula WT Kale-Pradhan PB Therapeutic dilemma of flucona-

zole prophylaxis in intensive care Ann Pharmacother 2002 36 155ndash9

115 Pelz RK Hendrix CW Swoboda SM et al Double-blind placebo-

controlled trial of fluconazole to prevent candidal infections in critically ill

surgical patients Ann Surg 2001 233 542ndash8

116 Eggimann P Francioli P Bille J et al Fluconazole prophylaxis

prevents intraabdominal candidiasis in high-risk surgical patients Crit

Care Med 1997 27 1066ndash72

117 Swoboda SM Merz WG Lipsetta PA Candidemia the impact of

antifungal prophylaxis in a surgical intensive care unitSurg Infect20034345ndash54

118 Todd JC OrsquoNeal VG Grady KP et al Reduction of secondary

mycotic infections in the trauma intensivie care unit with fluconazole

J Trauma 1991 31 1722ndash27

119 Jacobs S Price Evans DA Tariq M et al Fluconazole improves

survival in septic shock a randomized double-blind prospective studyCrit

Care Med 2003 31 1938ndash46

120 Zervos EE Fink GW Norman JG et al Fluconazole increases

bactericidal activity of neutrophils through non-cytokine-mediated path-

way J Trauma 1996 41 465ndash70

121 AblesAZBlumerNAValainisGTetal Fluconazoleprophylaxis of

severe Candida infection in trauma and postsurgical patients a prospec-

tive double-blind randomised placebo-controlled trial Infect Dis Clin

Pract 2000 9 169ndash75

122 Kam LW Lin JD Management of systemic candidal infections in

the intensive care unit Am J Health Syst Pharm 2002 59 33ndash41

123 Rocco TR Reinert SE Simms HH Effects of fluconazole admin-

istration in critically ill patients analysis of bacterial and fungal resistance

Arch Surg 2000 135 160ndash5

124 Tortorano AM Caspani L Rigoni AL et al Candidosis in the inten-

sive care unit a 20-year survey J Hosp Infect 2004 57 8ndash13

125 EggimannPGarbino J Pittet DManagement ofCandida species

infections in critically ill patients Lancet Infect Dis 2003 3 772ndash85

Review

407

126 EggimannPGarbinoJPittetDEpidemiologyofCandida species

infections incritically ill non-immunosuppressedpatientsLancet InfectDis

2003 3 685ndash702

127 Martins MD Lozano-Chiu M Rex JH Declining rates of oropha-

ryngeal candidiasis and carriage of Candida albicans associated with

trends toward reduced rates of carriage of fluconazole-resistant C albi-

cans in human immunodeficiency virus-infected patients Clin Infect Dis

1998 27 1291ndash4

128 Powderly WG Finkelstein D Feinberg J et al A randomized trial

comparing fluconazole with clotrimazole troches for the prevention of fun-

gal infections in patients with advanced human immunodeficiency virus

infection NIAID AIDS Clinical Trials Group N Engl J Med 1995 332700ndash5

129 Leen CL Dunbar EM Ellis ME et al Once-weekly fluconazole to

prevent recurrenceof oropharyngeal candidiasis inpatientswithAIDSand

AIDS-related complex a double-blind placebo-controlled study J Infect

1990 21 55ndash60

130 Stevens DA Greene SI Lang OS Thrush can be prevented in

patients with acquired immunodeficiency syndrome and the acquired

immunodeficiency syndrome-related complex Randomized double-

blind placebo-controlled study of 100-mg oral fluconazole daily Arch

Intern Med 1991 151 2458ndash64

131 Just-Nubling G Gentschew G Meissner K Fluconazole prophy-

laxis of recurrent oral candidiasis inHIV-positive patientsEur JClinMicro-

biol Infect Dis 1991 10 917ndash21

132 Marriott DJ Jones PD Hoy JF et al Fluconazole once a week as

secondary prophylaxis against oropharyngeal candidiasis in HIV-infected

patients A double-blind placebo-controlled studyMed J Aust 1993 158312ndash16

133 Schuman P Capps L Peng G et al Weekly fluconazole for the

prevention ofmucosal candidiasis inwomenwithHIV infection A random-

ized double-blind placebo-controlled trial Terry Beirn Community Pro-

grams for Clinical Research on AIDSAnn InternMed 1997 126 689ndash96

134 Havlir DV DubeMPMcCutchan JA et al Prophylaxis with weekly

versus daily fluconazole for fungal infections in patients with AIDS Clin

Infect Dis 1998 27 1369ndash75

135 Pagani JL Chave JP Casjka C et al Efficacy tolerability and

development of resistance in HIV-positive patients treated with flucona-

zole for secondary prevention of oropharyngeal candidiasis a random-

ized double-blind placebo-controlled trial JAntimicrobChemother 2002

50 231ndash40

136 Vazquez JA Peng G Sobel JD et al Evolution of antifungal sus-

ceptibility amongCandidaspecies isolates recovered fromhuman immun-

odeficiency virus-infected women receiving fluconazole prophylaxis Clin

Infect Dis 2001 33 1069ndash75

137 Delfraissy JF Prise en charge therapeutique des patients infectespas le VIH Rapport Delfraissy Paris Flammarion 2004

138 DePauwBERaemaekers JMDonnelly JPet al Anopenstudyon

the safety and efficacy of fluconazole in the treatment of disseminated

Candida infections in patients treated for hematological malignancy Ann

Hematol 1995 70 83ndash7

139 Anaissie EJ Vartivarian SE Abi-Said D et al Fluconazole versus

amphotericin B in the treatment of hematogenous candidiasis a matched

cohort study Am J Med 1996 101 170ndash6

140 Anaissie EJ Darouiche RO Abi-Said D et al Management of

invasive candidal infections results of a prospective randomized multi-

center study of fluconazole versus amphotericin B and review of the

literature Clin Infect Dis 1996 23 964ndash72

141 Myoken Y Kyo T Kohara T et al Breakthrough fungemia caused

by azole-resistant Candida albicans in neutropenic patients with acute

leukemia Clin Infect Dis 2003 36 1496ndash7

142 Anttila VJ FarkkilaM JanssonSE et al Diagnostic laparoscopy in

patientswith acute leukemiaandsuspectedhepatic candidiasisEur JClin

Microbiol Infect Dis 1997 16 637ndash43

143 Anaissie E Bodey GP Kantarjian H et al Fluconazole therapy for

chronic disseminated candidiasis in patients with leukemia and prior

amphotericin B therapy Am J Med 1991 91 142ndash50

144 KauffmanCA BradleySFRossSC et al Hepatosplenic candidia-

sis successful treatment with fluconazole Am J Med 1991 91 137ndash41

145 Kontoyiannis DP Luna MA Samuels BI et al Hepatosplenic can-

didiasis A manifestation of chronic disseminated candidiasis Infect Dis

Clin North Am 2000 14 721ndash39

146 Graninger W Presteril E Schneeweiss B et al Treatment of

Candida albicans fungaemia with fluconazole J Infect 1993 26 133ndash46

147 Phillips P Shafran S Garber G et al Multicenter randomized trial

of fluconazole versus amphotericin B for treatment of candidemia in

non-neutropenic patients Canadian Candidemia Study Group Eur J

Clin Microbiol Infect Dis 1997 16 337ndash45

148 Rex JH Bennett JE Sugar AM et alA randomized trial comparing

fluconazolewithamphotericinB for the treatmentof candidemia inpatients

without neutropenia Candidemia Study Group and the National Institute

N Engl J Med 1994 331 1325ndash30

149 Abele-Horn M Kopp A Sternberg U et al A randomized study

comparing fluconazolewith amphotericinB5-flucytosine for the treatment

of systemic Candida infections in intensive care patients Infection 1996

24 426ndash32

150 Nguyen MH Peacock JE Jr Tanner DC et al Therapeutic

approaches in patients with candidemia Evaluation in a multicenter

prospective observational study Arch Intern Med 1995 155 2429ndash35

151 Rex JH Pappas PG Karchmer AW et al A randomized and

blinded multicenter trial of high-dose fluconazole plus placebo versus flu-

conazole plus amphotericin B as therapy for candidemia and its con-

sequences in non-neutropenic subjectsClin Infect Dis 2003 36 1221ndash8

152 Mora-Duarte J Betts R Rotstein C et al Comparison of

caspofungin and amphotericin B for invasive candidiasis N Engl J Med

2002 347 2020ndash9

153 Sugar AM Saunders C Diamond RD et al Successful treatment

of Candida osteomyelitis with fluconazole A noncomparative study of

two patients Diagn Microbiol Infect Dis 1990 13 517ndash20

154 Tang C Successful treatment of Candida albicans osteomyelitis

with fluconazole J Infect 1993 26 89ndash92

155 LafontAOliveAGelmanMet alCandidaalbicansspondylodisci-

tis and vertebral osteomyelitis in patients with intravenous heroin drug

addiction Report of 3 new cases J Rheumatol 1994 21 953ndash6

156 Hennequin C Bouree P Hiesse C et al Spondylodiskitis due to

Candida albicans report of two patients who were successfully treated

with fluconazole and review of the literature Clin Infect Dis 1996 23176ndash8

157 Jonnalagadda S VeerabaguMP Rakela J et alCandida albicans

osteomyelitis in a liver transplant recipient a case report and review of the

literature Transplantation 1996 62 1182ndash4

158 Rossel P Schonheyder HC Nielsen H Fluconazole therapy

inCandidaalbicansspondylodiscitisScandJ InfectDis199830 527ndash30

159 TurnerDLJohnsonSARuleSASuccessful treatmentof candidal

osteomyelitis with fluconazole following failure with liposomal ampho-

tericin B J Infect 1999 38 51ndash3

160 El-Zaatari MM Hulten K Fares Y et al Successful treatment of

Candida albicans osteomyelitis of the spine with fluconazole and surgical

debridement case report J Chemother 2002 14 627ndash30

161 Seravalli L Van Linthoudt D Bernet C et al Candida glabrata

spinal osteomyelitis involving two contiguous lumbar vertebrae a case

report and review of the literature Diagn Microbiol Infect Dis 2003 45137ndash41

162 Garbino J Schnyder I LewDP et al An unusual cause of vertebral

osteomyelitis Candida species Scand J Infect Dis 2003 35 288ndash91

163 TunkelARThomasCYWispelweyBCandidaprostheticarthritis

report of a case treated with fluconazole and review of the literature Am J

Med 1993 94 100ndash3

Review

408

164 CushingRD FulgenziWR Synovial fluid levels of fluconazole in a

patient with Candida parapsilosis prosthetic joint infection who had an

excellent clinical response J Arthroplasty 1997 12 950

165 Fukasawa N Shirakura K Candida arthritis after total knee

arthroplastymdasha case of successful treatment without prosthesis removal

Acta Orthop Scand 1997 68 306ndash7

166 Lerch K Kalteis T Schubert T et al Prosthetic joint infections with

osteomyelitis due to Candida albicans Mycoses 2003 46 462ndash6

167 Clancy CJ Nguyen MH Morris AJ Candidal mediastinitis an

emerging clinical entity Clin Infect Dis 1997 25 608ndash13

168 PetrikkosGSkiadaA SabatakouH et al Case report Successful

treatment of two cases of post-surgical sternal osteomyelitis due to

Candida krusei and Candida albicans respectively with high doses of

triazoles (fluconazole itraconazole) Mycoses 2001 44 422ndash5

169 Weers-Pothoff GHavermans JF Kamphuis J et alCandida tropi-

calis arthritis in a patient with acutemyeloid leukemia successfully treated

with fluconazole case report and review of the literature Infection 1997

25 109ndash11

170 Laatikainen L TuominenM vonDickhoff K Treatment of endoge-

nous fungal endophthalmitis with systemic fluconazole with or without

vitrectomy Am J Ophthalmol 1992 113 205ndash7

171 Borne MJ Elliott JH OrsquoDay DM Ocular fluconazole treatment of

Candidaparapsilosisendophthalmitis after failed intravitreal amphotericin

B Arch Ophthalmol 1993 111 1326ndash7

172 Zarbin MA Becker E Witcher J et al Treatment of presumed

fungal endophthalmitis with oral fluconazole Ophthalmic Surg Lasers

1996 27 628ndash31

173 WongVK TasmanWEagleRC et al BilateralCandida parapsilo-

sis endophthalmitis Arch Ophthalmol 1997 115 670ndash2

174 Kauffman CA Bradley SF Vine AK Candida endophthalmitis

associated with intraocular lens implantation efficacy of fluconazole ther-

apy Mycoses 1993 36 13ndash17

175 del Palacio A Cuetara MS Ferro M et al Fluconazole in the man-

agement of endophthalmitis in disseminated candidosis of heroin addicts

Mycoses 1993 36 193ndash9

176 Luttrull JK Wan WL Kubak BM et al Treatment of ocular fungal

infections with oral fluconazole Am J Ophthalmol 1995 119 477ndash81

177 Akler ME Vellend H McNeely DM et al Use of fluconazole in the

treatment of candidal endophthalmitis Clin Infect Dis 1995 20 657ndash64

178 Christmas NJ Smiddy WE Vitrectomy and systemic fluconazole

for treatment of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1996 27 1012ndash18

179 EssmanTFFlynnHWSmiddyWEet al Treatment outcomes in a

10-year study of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1997 28 185ndash94

180 Martinez-Vazquez C Fernandez-Ulloa J Bordon J et al Candida

albicans endophthalmitis in brown heroin addicts response to early vit-

rectomyprecededand followedbyantifungal therapyClin InfectDis1998

27 1130ndash3

181 Aleixo MJ Caldeira L Ferreira ML Candida albicans meningitis

clinical case J Infect 2000 40 191ndash2

182 InoueY YozuR Ueda T et al A case report ofCandida parapsilo-

sis endocarditis J Heart Valve Dis 1998 7 240ndash2

183 Isalska BJ Stanbridge TN Fluconazole in the treatment of candi-

dal prosthetic valve endocarditis BMJ 1988 297 178ndash9

184 Martino P Meloni G Cassone A Candidal endocarditis and treat-

ment with fluconazole and granulocyte-macrophage colony-stimulating

factor Ann Intern Med 1990 112 966ndash7

185 Roupie E Darmon JY Brochard L et al Fluconazole therapy of

candidal native valveendocarditisEur JClinMicrobiol InfectDis199110458ndash9

186 Hernandez JA Gonzalez-Moreno M Llibre JM et al Candidal

mitral endocarditis and long-term treatment with fluconazole in a patient

with human immunodeficiency virus infection Clin Infect Dis 1992 151062ndash3

187 Venditti MDeBernardis FMicozzi A et al Fluconazole treatment

of catheter-related right-sided endocarditis caused by Candida albicans

and associated with endophthalmitis and folliculitis Clin Infect Dis 1992

14 422ndash6

188 Wallbridge DR McCartney AC Richardson MD Fluconazole in

the treatment ofCandidaprosthetic valveendocarditisMycoses199336259ndash61

189 Otaki M Kitamura N Candida prosthetic valve endocarditis An

autopsy review Int Surg 1993 78 252ndash3

190 Czwerwiec FS Bilsker MS Kamerman ML et al Long-term sur-

vival after fluconazole therapy of candidal prosthetic valve endocarditis

Am J Med 1993 94 545ndash6

191 Thakur RK Skelcy KM Kahn RN et al Successful treatment of

Candida prosthetic valve endocarditis with a combination of fluconazole

and amphotericin B Crit Care Med 1994 22 712ndash14

192 Cancelas JA Lopez JCabezudoE et al Native valve endocarditis

due toCandida parapsilosis a late complication after bonemarrow trans-

plantation-related fungemia Bone Marrow Transplant 1994 13 333ndash4

193 Zahid MA Klotz SA Hinthorn DR Medical treatment of recurrent

candidemia in a patient with probable Candida parapsilosis prosthetic

valve endocarditis Chest 1994 105 1597ndash8

194 Wells CJ Leech G Lever AM et al Treatment of native valve

Candida endocarditis with fluconazole J Infect 1995 31 233ndash5

195 Gilbert HM Peters ED Lang SJ et al Successful treatment of

fungal prosthetic valve endocarditis case report and review Clin Infect

Dis 1996 22 348ndash54

196 Nguyen MH Nguyen ML Yu VL et al Candida prosthetic valve

endocarditis prospective study of six cases and review of the literature

Clin Infect Dis 1996 22 262ndash7

197 Lejko-Zupanc T Kozelj M A case of recurrent Candida parapsilo-

sis prosthetic valve endocarditis cure bymedical treatment alone J Infect

1997 35 81ndash2

198 Joly V BelmatougN Leperre A et al Pacemaker endocarditis due

to Candida albicans case report and review Clin Infect Dis 1997 251359ndash62

199 Rex JH Walsh T Sobel JD et al Practice guidelines for the treat-

mentof candidiasis InfectiousDiseasesSocietyofAmericaClin InfectDis

2000 30 662ndash78

200 Baddour LM Long-term suppressive therapy for Candida para-

psilosis-induced prosthetic valve endocarditis Mayo Clin Proc 1995

70 773ndash5

201 Melgar GR Nasser RM Gordon SM Fungal prosthetic valve

endocarditis in 16 patients An 11-year experience in a tertiary care hos-

pital Medicine 1997 76 94ndash103

202 Dupont H Paugam-Burtz C Muller-Serieys C et al Predictive

factors of mortality due to polymicrobial peritonitis with Candida isolation

in peritoneal fluid in critically ill patients Arch Surg 2002 137 1341ndash6

203 Lee SC FungCP ChenHY et alCandida peritonitis due to peptic

ulcer perforation incidence rate risk factors prognosis and susceptibility

to fluconazole and amphotericin B Diagn Microbiol Infect Dis 2002 4423ndash7

204 Levine J Bernard DB Idelson BA et al Fungal peritonitis compli-

cating continuous ambulatory peritoneal dialysis successful treatment

with fluconazole a new orally active antifungal agent Am J Med 1989

86 825ndash7

205 Michel C Courdavault L al Khayat R et al Fungal peritonitis in

patients on peritoneal dialysis Am J Nephrol 1994 14 113ndash20

206 WangAYYuAWLi PKet al Factors predicting outcomeof fungal

peritonitis in peritoneal dialysis analysis of a 9-year experience of fungal

peritonitis in a single center Am J Kidney Dis 2000 36 1183ndash92

207 Hawkins JL Baddour LM Candida lusitaniae infections in the era

of fluconazole availability Clin Infect Dis 2003 36 14ndash18

Review

409

208 KauffmanCAVazquezJASobel JDetal Prospectivemulticenter

surveillance study of funguria in hospitalized patients The National Insti-

tute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group

Clin Infect Dis 2000 30 14ndash18

209 Sobel JD Kauffman CA McKinsey D et al Candiduria a random-

ized double-blind study of treatment with fluconazole and placebo The

National Institute of Allergy and Infectious Diseases (NIAID) Mycoses

Study Group Clin Infect Dis 2000 30 19ndash24

210 LundstromTSobel JNosocomial candiduria a reviewClin Infect

Dis 2001 32 1602ndash7

211 Kaufman D Boyle R Hazen KC et al Fluconazole prophylaxis

against fungal colonization and infection in preterm infants N Engl J

Med 2001 345 1660ndash6

212 Kicklighter SD Springer SC Cox T et al Fluconazole for the pro-

phylaxis against candidal rectal colonization in the very low birth weight

infant Pediatrics 2001 107 293ndash8

213 McGuire W Clerihew L Austin N Prophylactic intravenous anti-

fungal agents to prevent mortality and morbidity in very low birth weight

infants Cochrane Database Syst Rev 2004 CD003850

214 Agarwal JBansalSMalikGKetal Trends inneonatal septicemia

emergence of non-albicans Candida Indian Pediatr 2004 41 712ndash15

215 FasanoCOrsquoKeefe JGibbsD Fluconazole treatment of neonates

and infants with severe fungal infections not treatable with conventional

agents Eur J Clin Microbiol Infect Dis 1994 13 351ndash4

216 Wainer S Cooper PA Gouws H et al Prospective study of flu-

conazole therapy in systemicneonatal fungal infectionPediatr InfectDis J

1997 16 763ndash7

217 Huang YC Lin TY Lien RI et al Fluconazole therapy in neonatal

candidemia Am J Perinatol 2000 17 411ndash15

218 Huttova M Hartmanova I Kralinsky K et al Candida fungemia in

neonates treated with fluconazole report of forty cases including eight

with meningitis Pediatr Infect Dis J 1998 17 1012ndash15

219 Gurpinar AN Balkan E Kilic N et al Fluconazole treatment of

neonates and infants with severe fungal infections J Int Med Res 1997

25 214ndash18

220 Driessen M Ellis JB Muwazi F et al The treatment of systemic

candidiasis in neonates with oral fluconazole Ann Trop Pediatr 1997 17263ndash71

221 Driessen M Ellis JB Cooper PA et al Fluconazole vs

amphotericin B for the treatment of neonatal fungal septicemia

a prospective randomized trial Pediatr Infect Dis J 1997 151107ndash12

222 Marr B Gross S Cunningham C et al Candidal sepsis and

meningitis in a very-low-birth-weight infant successfully treated with flu-

conazole and flucytosine Clin Infect Dis 1994 19 795ndash6

223 Oleinik EM Della-Latta P Rinaldi MG et al Candida lusitaniae

osteomyelitis in a premature infant Am J Perinatol 1993 10 313ndash15

224 Mondal RK Singhi SC Chakrabarti A Randomized comparison

between fluconazole and itraconazole for the treatment of candidemia in a

pediatric intensive care unit a preliminary study Pediatr Crit Care Med

2004 5 561ndash5

225 Viscoli C Castagnola E Fioredda F et al Fluconazole in the treat-

ment of candidiasis in immunocompromised children Antimicrob Agents

Chemother 1991 35 365ndash7

226 Decruyenaere J Colardyn F Vogelaers D et al Combined use of

fluconazole and selective digestive decontamination in the prevention of

fungal infection after adult liver transplantation Transplant Proc 1995 273515ndash16

227 Koh LP Kurup A Goh YT et al Randomized trial of fluconazole

versus low-dose amphotericin B in prophylaxis against fungal infections in

patients undergoing hematopoietic stem cell transplantationAmJHema-

tol 2002 71 260ndash7

228 Gluckman E Esperou-Bourdeau H Ribaud P et al Comparaison

entre le fluconazole et le ketoconazole pour la prophylaxie des infections

fongiques chez les patients traites par greffe de moelle allogenique Cah

Oncol 1993 2 167ndash9

Review

410

126 EggimannPGarbinoJPittetDEpidemiologyofCandida species

infections incritically ill non-immunosuppressedpatientsLancet InfectDis

2003 3 685ndash702

127 Martins MD Lozano-Chiu M Rex JH Declining rates of oropha-

ryngeal candidiasis and carriage of Candida albicans associated with

trends toward reduced rates of carriage of fluconazole-resistant C albi-

cans in human immunodeficiency virus-infected patients Clin Infect Dis

1998 27 1291ndash4

128 Powderly WG Finkelstein D Feinberg J et al A randomized trial

comparing fluconazole with clotrimazole troches for the prevention of fun-

gal infections in patients with advanced human immunodeficiency virus

infection NIAID AIDS Clinical Trials Group N Engl J Med 1995 332700ndash5

129 Leen CL Dunbar EM Ellis ME et al Once-weekly fluconazole to

prevent recurrenceof oropharyngeal candidiasis inpatientswithAIDSand

AIDS-related complex a double-blind placebo-controlled study J Infect

1990 21 55ndash60

130 Stevens DA Greene SI Lang OS Thrush can be prevented in

patients with acquired immunodeficiency syndrome and the acquired

immunodeficiency syndrome-related complex Randomized double-

blind placebo-controlled study of 100-mg oral fluconazole daily Arch

Intern Med 1991 151 2458ndash64

131 Just-Nubling G Gentschew G Meissner K Fluconazole prophy-

laxis of recurrent oral candidiasis inHIV-positive patientsEur JClinMicro-

biol Infect Dis 1991 10 917ndash21

132 Marriott DJ Jones PD Hoy JF et al Fluconazole once a week as

secondary prophylaxis against oropharyngeal candidiasis in HIV-infected

patients A double-blind placebo-controlled studyMed J Aust 1993 158312ndash16

133 Schuman P Capps L Peng G et al Weekly fluconazole for the

prevention ofmucosal candidiasis inwomenwithHIV infection A random-

ized double-blind placebo-controlled trial Terry Beirn Community Pro-

grams for Clinical Research on AIDSAnn InternMed 1997 126 689ndash96

134 Havlir DV DubeMPMcCutchan JA et al Prophylaxis with weekly

versus daily fluconazole for fungal infections in patients with AIDS Clin

Infect Dis 1998 27 1369ndash75

135 Pagani JL Chave JP Casjka C et al Efficacy tolerability and

development of resistance in HIV-positive patients treated with flucona-

zole for secondary prevention of oropharyngeal candidiasis a random-

ized double-blind placebo-controlled trial JAntimicrobChemother 2002

50 231ndash40

136 Vazquez JA Peng G Sobel JD et al Evolution of antifungal sus-

ceptibility amongCandidaspecies isolates recovered fromhuman immun-

odeficiency virus-infected women receiving fluconazole prophylaxis Clin

Infect Dis 2001 33 1069ndash75

137 Delfraissy JF Prise en charge therapeutique des patients infectespas le VIH Rapport Delfraissy Paris Flammarion 2004

138 DePauwBERaemaekers JMDonnelly JPet al Anopenstudyon

the safety and efficacy of fluconazole in the treatment of disseminated

Candida infections in patients treated for hematological malignancy Ann

Hematol 1995 70 83ndash7

139 Anaissie EJ Vartivarian SE Abi-Said D et al Fluconazole versus

amphotericin B in the treatment of hematogenous candidiasis a matched

cohort study Am J Med 1996 101 170ndash6

140 Anaissie EJ Darouiche RO Abi-Said D et al Management of

invasive candidal infections results of a prospective randomized multi-

center study of fluconazole versus amphotericin B and review of the

literature Clin Infect Dis 1996 23 964ndash72

141 Myoken Y Kyo T Kohara T et al Breakthrough fungemia caused

by azole-resistant Candida albicans in neutropenic patients with acute

leukemia Clin Infect Dis 2003 36 1496ndash7

142 Anttila VJ FarkkilaM JanssonSE et al Diagnostic laparoscopy in

patientswith acute leukemiaandsuspectedhepatic candidiasisEur JClin

Microbiol Infect Dis 1997 16 637ndash43

143 Anaissie E Bodey GP Kantarjian H et al Fluconazole therapy for

chronic disseminated candidiasis in patients with leukemia and prior

amphotericin B therapy Am J Med 1991 91 142ndash50

144 KauffmanCA BradleySFRossSC et al Hepatosplenic candidia-

sis successful treatment with fluconazole Am J Med 1991 91 137ndash41

145 Kontoyiannis DP Luna MA Samuels BI et al Hepatosplenic can-

didiasis A manifestation of chronic disseminated candidiasis Infect Dis

Clin North Am 2000 14 721ndash39

146 Graninger W Presteril E Schneeweiss B et al Treatment of

Candida albicans fungaemia with fluconazole J Infect 1993 26 133ndash46

147 Phillips P Shafran S Garber G et al Multicenter randomized trial

of fluconazole versus amphotericin B for treatment of candidemia in

non-neutropenic patients Canadian Candidemia Study Group Eur J

Clin Microbiol Infect Dis 1997 16 337ndash45

148 Rex JH Bennett JE Sugar AM et alA randomized trial comparing

fluconazolewithamphotericinB for the treatmentof candidemia inpatients

without neutropenia Candidemia Study Group and the National Institute

N Engl J Med 1994 331 1325ndash30

149 Abele-Horn M Kopp A Sternberg U et al A randomized study

comparing fluconazolewith amphotericinB5-flucytosine for the treatment

of systemic Candida infections in intensive care patients Infection 1996

24 426ndash32

150 Nguyen MH Peacock JE Jr Tanner DC et al Therapeutic

approaches in patients with candidemia Evaluation in a multicenter

prospective observational study Arch Intern Med 1995 155 2429ndash35

151 Rex JH Pappas PG Karchmer AW et al A randomized and

blinded multicenter trial of high-dose fluconazole plus placebo versus flu-

conazole plus amphotericin B as therapy for candidemia and its con-

sequences in non-neutropenic subjectsClin Infect Dis 2003 36 1221ndash8

152 Mora-Duarte J Betts R Rotstein C et al Comparison of

caspofungin and amphotericin B for invasive candidiasis N Engl J Med

2002 347 2020ndash9

153 Sugar AM Saunders C Diamond RD et al Successful treatment

of Candida osteomyelitis with fluconazole A noncomparative study of

two patients Diagn Microbiol Infect Dis 1990 13 517ndash20

154 Tang C Successful treatment of Candida albicans osteomyelitis

with fluconazole J Infect 1993 26 89ndash92

155 LafontAOliveAGelmanMet alCandidaalbicansspondylodisci-

tis and vertebral osteomyelitis in patients with intravenous heroin drug

addiction Report of 3 new cases J Rheumatol 1994 21 953ndash6

156 Hennequin C Bouree P Hiesse C et al Spondylodiskitis due to

Candida albicans report of two patients who were successfully treated

with fluconazole and review of the literature Clin Infect Dis 1996 23176ndash8

157 Jonnalagadda S VeerabaguMP Rakela J et alCandida albicans

osteomyelitis in a liver transplant recipient a case report and review of the

literature Transplantation 1996 62 1182ndash4

158 Rossel P Schonheyder HC Nielsen H Fluconazole therapy

inCandidaalbicansspondylodiscitisScandJ InfectDis199830 527ndash30

159 TurnerDLJohnsonSARuleSASuccessful treatmentof candidal

osteomyelitis with fluconazole following failure with liposomal ampho-

tericin B J Infect 1999 38 51ndash3

160 El-Zaatari MM Hulten K Fares Y et al Successful treatment of

Candida albicans osteomyelitis of the spine with fluconazole and surgical

debridement case report J Chemother 2002 14 627ndash30

161 Seravalli L Van Linthoudt D Bernet C et al Candida glabrata

spinal osteomyelitis involving two contiguous lumbar vertebrae a case

report and review of the literature Diagn Microbiol Infect Dis 2003 45137ndash41

162 Garbino J Schnyder I LewDP et al An unusual cause of vertebral

osteomyelitis Candida species Scand J Infect Dis 2003 35 288ndash91

163 TunkelARThomasCYWispelweyBCandidaprostheticarthritis

report of a case treated with fluconazole and review of the literature Am J

Med 1993 94 100ndash3

Review

408

164 CushingRD FulgenziWR Synovial fluid levels of fluconazole in a

patient with Candida parapsilosis prosthetic joint infection who had an

excellent clinical response J Arthroplasty 1997 12 950

165 Fukasawa N Shirakura K Candida arthritis after total knee

arthroplastymdasha case of successful treatment without prosthesis removal

Acta Orthop Scand 1997 68 306ndash7

166 Lerch K Kalteis T Schubert T et al Prosthetic joint infections with

osteomyelitis due to Candida albicans Mycoses 2003 46 462ndash6

167 Clancy CJ Nguyen MH Morris AJ Candidal mediastinitis an

emerging clinical entity Clin Infect Dis 1997 25 608ndash13

168 PetrikkosGSkiadaA SabatakouH et al Case report Successful

treatment of two cases of post-surgical sternal osteomyelitis due to

Candida krusei and Candida albicans respectively with high doses of

triazoles (fluconazole itraconazole) Mycoses 2001 44 422ndash5

169 Weers-Pothoff GHavermans JF Kamphuis J et alCandida tropi-

calis arthritis in a patient with acutemyeloid leukemia successfully treated

with fluconazole case report and review of the literature Infection 1997

25 109ndash11

170 Laatikainen L TuominenM vonDickhoff K Treatment of endoge-

nous fungal endophthalmitis with systemic fluconazole with or without

vitrectomy Am J Ophthalmol 1992 113 205ndash7

171 Borne MJ Elliott JH OrsquoDay DM Ocular fluconazole treatment of

Candidaparapsilosisendophthalmitis after failed intravitreal amphotericin

B Arch Ophthalmol 1993 111 1326ndash7

172 Zarbin MA Becker E Witcher J et al Treatment of presumed

fungal endophthalmitis with oral fluconazole Ophthalmic Surg Lasers

1996 27 628ndash31

173 WongVK TasmanWEagleRC et al BilateralCandida parapsilo-

sis endophthalmitis Arch Ophthalmol 1997 115 670ndash2

174 Kauffman CA Bradley SF Vine AK Candida endophthalmitis

associated with intraocular lens implantation efficacy of fluconazole ther-

apy Mycoses 1993 36 13ndash17

175 del Palacio A Cuetara MS Ferro M et al Fluconazole in the man-

agement of endophthalmitis in disseminated candidosis of heroin addicts

Mycoses 1993 36 193ndash9

176 Luttrull JK Wan WL Kubak BM et al Treatment of ocular fungal

infections with oral fluconazole Am J Ophthalmol 1995 119 477ndash81

177 Akler ME Vellend H McNeely DM et al Use of fluconazole in the

treatment of candidal endophthalmitis Clin Infect Dis 1995 20 657ndash64

178 Christmas NJ Smiddy WE Vitrectomy and systemic fluconazole

for treatment of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1996 27 1012ndash18

179 EssmanTFFlynnHWSmiddyWEet al Treatment outcomes in a

10-year study of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1997 28 185ndash94

180 Martinez-Vazquez C Fernandez-Ulloa J Bordon J et al Candida

albicans endophthalmitis in brown heroin addicts response to early vit-

rectomyprecededand followedbyantifungal therapyClin InfectDis1998

27 1130ndash3

181 Aleixo MJ Caldeira L Ferreira ML Candida albicans meningitis

clinical case J Infect 2000 40 191ndash2

182 InoueY YozuR Ueda T et al A case report ofCandida parapsilo-

sis endocarditis J Heart Valve Dis 1998 7 240ndash2

183 Isalska BJ Stanbridge TN Fluconazole in the treatment of candi-

dal prosthetic valve endocarditis BMJ 1988 297 178ndash9

184 Martino P Meloni G Cassone A Candidal endocarditis and treat-

ment with fluconazole and granulocyte-macrophage colony-stimulating

factor Ann Intern Med 1990 112 966ndash7

185 Roupie E Darmon JY Brochard L et al Fluconazole therapy of

candidal native valveendocarditisEur JClinMicrobiol InfectDis199110458ndash9

186 Hernandez JA Gonzalez-Moreno M Llibre JM et al Candidal

mitral endocarditis and long-term treatment with fluconazole in a patient

with human immunodeficiency virus infection Clin Infect Dis 1992 151062ndash3

187 Venditti MDeBernardis FMicozzi A et al Fluconazole treatment

of catheter-related right-sided endocarditis caused by Candida albicans

and associated with endophthalmitis and folliculitis Clin Infect Dis 1992

14 422ndash6

188 Wallbridge DR McCartney AC Richardson MD Fluconazole in

the treatment ofCandidaprosthetic valveendocarditisMycoses199336259ndash61

189 Otaki M Kitamura N Candida prosthetic valve endocarditis An

autopsy review Int Surg 1993 78 252ndash3

190 Czwerwiec FS Bilsker MS Kamerman ML et al Long-term sur-

vival after fluconazole therapy of candidal prosthetic valve endocarditis

Am J Med 1993 94 545ndash6

191 Thakur RK Skelcy KM Kahn RN et al Successful treatment of

Candida prosthetic valve endocarditis with a combination of fluconazole

and amphotericin B Crit Care Med 1994 22 712ndash14

192 Cancelas JA Lopez JCabezudoE et al Native valve endocarditis

due toCandida parapsilosis a late complication after bonemarrow trans-

plantation-related fungemia Bone Marrow Transplant 1994 13 333ndash4

193 Zahid MA Klotz SA Hinthorn DR Medical treatment of recurrent

candidemia in a patient with probable Candida parapsilosis prosthetic

valve endocarditis Chest 1994 105 1597ndash8

194 Wells CJ Leech G Lever AM et al Treatment of native valve

Candida endocarditis with fluconazole J Infect 1995 31 233ndash5

195 Gilbert HM Peters ED Lang SJ et al Successful treatment of

fungal prosthetic valve endocarditis case report and review Clin Infect

Dis 1996 22 348ndash54

196 Nguyen MH Nguyen ML Yu VL et al Candida prosthetic valve

endocarditis prospective study of six cases and review of the literature

Clin Infect Dis 1996 22 262ndash7

197 Lejko-Zupanc T Kozelj M A case of recurrent Candida parapsilo-

sis prosthetic valve endocarditis cure bymedical treatment alone J Infect

1997 35 81ndash2

198 Joly V BelmatougN Leperre A et al Pacemaker endocarditis due

to Candida albicans case report and review Clin Infect Dis 1997 251359ndash62

199 Rex JH Walsh T Sobel JD et al Practice guidelines for the treat-

mentof candidiasis InfectiousDiseasesSocietyofAmericaClin InfectDis

2000 30 662ndash78

200 Baddour LM Long-term suppressive therapy for Candida para-

psilosis-induced prosthetic valve endocarditis Mayo Clin Proc 1995

70 773ndash5

201 Melgar GR Nasser RM Gordon SM Fungal prosthetic valve

endocarditis in 16 patients An 11-year experience in a tertiary care hos-

pital Medicine 1997 76 94ndash103

202 Dupont H Paugam-Burtz C Muller-Serieys C et al Predictive

factors of mortality due to polymicrobial peritonitis with Candida isolation

in peritoneal fluid in critically ill patients Arch Surg 2002 137 1341ndash6

203 Lee SC FungCP ChenHY et alCandida peritonitis due to peptic

ulcer perforation incidence rate risk factors prognosis and susceptibility

to fluconazole and amphotericin B Diagn Microbiol Infect Dis 2002 4423ndash7

204 Levine J Bernard DB Idelson BA et al Fungal peritonitis compli-

cating continuous ambulatory peritoneal dialysis successful treatment

with fluconazole a new orally active antifungal agent Am J Med 1989

86 825ndash7

205 Michel C Courdavault L al Khayat R et al Fungal peritonitis in

patients on peritoneal dialysis Am J Nephrol 1994 14 113ndash20

206 WangAYYuAWLi PKet al Factors predicting outcomeof fungal

peritonitis in peritoneal dialysis analysis of a 9-year experience of fungal

peritonitis in a single center Am J Kidney Dis 2000 36 1183ndash92

207 Hawkins JL Baddour LM Candida lusitaniae infections in the era

of fluconazole availability Clin Infect Dis 2003 36 14ndash18

Review

409

208 KauffmanCAVazquezJASobel JDetal Prospectivemulticenter

surveillance study of funguria in hospitalized patients The National Insti-

tute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group

Clin Infect Dis 2000 30 14ndash18

209 Sobel JD Kauffman CA McKinsey D et al Candiduria a random-

ized double-blind study of treatment with fluconazole and placebo The

National Institute of Allergy and Infectious Diseases (NIAID) Mycoses

Study Group Clin Infect Dis 2000 30 19ndash24

210 LundstromTSobel JNosocomial candiduria a reviewClin Infect

Dis 2001 32 1602ndash7

211 Kaufman D Boyle R Hazen KC et al Fluconazole prophylaxis

against fungal colonization and infection in preterm infants N Engl J

Med 2001 345 1660ndash6

212 Kicklighter SD Springer SC Cox T et al Fluconazole for the pro-

phylaxis against candidal rectal colonization in the very low birth weight

infant Pediatrics 2001 107 293ndash8

213 McGuire W Clerihew L Austin N Prophylactic intravenous anti-

fungal agents to prevent mortality and morbidity in very low birth weight

infants Cochrane Database Syst Rev 2004 CD003850

214 Agarwal JBansalSMalikGKetal Trends inneonatal septicemia

emergence of non-albicans Candida Indian Pediatr 2004 41 712ndash15

215 FasanoCOrsquoKeefe JGibbsD Fluconazole treatment of neonates

and infants with severe fungal infections not treatable with conventional

agents Eur J Clin Microbiol Infect Dis 1994 13 351ndash4

216 Wainer S Cooper PA Gouws H et al Prospective study of flu-

conazole therapy in systemicneonatal fungal infectionPediatr InfectDis J

1997 16 763ndash7

217 Huang YC Lin TY Lien RI et al Fluconazole therapy in neonatal

candidemia Am J Perinatol 2000 17 411ndash15

218 Huttova M Hartmanova I Kralinsky K et al Candida fungemia in

neonates treated with fluconazole report of forty cases including eight

with meningitis Pediatr Infect Dis J 1998 17 1012ndash15

219 Gurpinar AN Balkan E Kilic N et al Fluconazole treatment of

neonates and infants with severe fungal infections J Int Med Res 1997

25 214ndash18

220 Driessen M Ellis JB Muwazi F et al The treatment of systemic

candidiasis in neonates with oral fluconazole Ann Trop Pediatr 1997 17263ndash71

221 Driessen M Ellis JB Cooper PA et al Fluconazole vs

amphotericin B for the treatment of neonatal fungal septicemia

a prospective randomized trial Pediatr Infect Dis J 1997 151107ndash12

222 Marr B Gross S Cunningham C et al Candidal sepsis and

meningitis in a very-low-birth-weight infant successfully treated with flu-

conazole and flucytosine Clin Infect Dis 1994 19 795ndash6

223 Oleinik EM Della-Latta P Rinaldi MG et al Candida lusitaniae

osteomyelitis in a premature infant Am J Perinatol 1993 10 313ndash15

224 Mondal RK Singhi SC Chakrabarti A Randomized comparison

between fluconazole and itraconazole for the treatment of candidemia in a

pediatric intensive care unit a preliminary study Pediatr Crit Care Med

2004 5 561ndash5

225 Viscoli C Castagnola E Fioredda F et al Fluconazole in the treat-

ment of candidiasis in immunocompromised children Antimicrob Agents

Chemother 1991 35 365ndash7

226 Decruyenaere J Colardyn F Vogelaers D et al Combined use of

fluconazole and selective digestive decontamination in the prevention of

fungal infection after adult liver transplantation Transplant Proc 1995 273515ndash16

227 Koh LP Kurup A Goh YT et al Randomized trial of fluconazole

versus low-dose amphotericin B in prophylaxis against fungal infections in

patients undergoing hematopoietic stem cell transplantationAmJHema-

tol 2002 71 260ndash7

228 Gluckman E Esperou-Bourdeau H Ribaud P et al Comparaison

entre le fluconazole et le ketoconazole pour la prophylaxie des infections

fongiques chez les patients traites par greffe de moelle allogenique Cah

Oncol 1993 2 167ndash9

Review

410

164 CushingRD FulgenziWR Synovial fluid levels of fluconazole in a

patient with Candida parapsilosis prosthetic joint infection who had an

excellent clinical response J Arthroplasty 1997 12 950

165 Fukasawa N Shirakura K Candida arthritis after total knee

arthroplastymdasha case of successful treatment without prosthesis removal

Acta Orthop Scand 1997 68 306ndash7

166 Lerch K Kalteis T Schubert T et al Prosthetic joint infections with

osteomyelitis due to Candida albicans Mycoses 2003 46 462ndash6

167 Clancy CJ Nguyen MH Morris AJ Candidal mediastinitis an

emerging clinical entity Clin Infect Dis 1997 25 608ndash13

168 PetrikkosGSkiadaA SabatakouH et al Case report Successful

treatment of two cases of post-surgical sternal osteomyelitis due to

Candida krusei and Candida albicans respectively with high doses of

triazoles (fluconazole itraconazole) Mycoses 2001 44 422ndash5

169 Weers-Pothoff GHavermans JF Kamphuis J et alCandida tropi-

calis arthritis in a patient with acutemyeloid leukemia successfully treated

with fluconazole case report and review of the literature Infection 1997

25 109ndash11

170 Laatikainen L TuominenM vonDickhoff K Treatment of endoge-

nous fungal endophthalmitis with systemic fluconazole with or without

vitrectomy Am J Ophthalmol 1992 113 205ndash7

171 Borne MJ Elliott JH OrsquoDay DM Ocular fluconazole treatment of

Candidaparapsilosisendophthalmitis after failed intravitreal amphotericin

B Arch Ophthalmol 1993 111 1326ndash7

172 Zarbin MA Becker E Witcher J et al Treatment of presumed

fungal endophthalmitis with oral fluconazole Ophthalmic Surg Lasers

1996 27 628ndash31

173 WongVK TasmanWEagleRC et al BilateralCandida parapsilo-

sis endophthalmitis Arch Ophthalmol 1997 115 670ndash2

174 Kauffman CA Bradley SF Vine AK Candida endophthalmitis

associated with intraocular lens implantation efficacy of fluconazole ther-

apy Mycoses 1993 36 13ndash17

175 del Palacio A Cuetara MS Ferro M et al Fluconazole in the man-

agement of endophthalmitis in disseminated candidosis of heroin addicts

Mycoses 1993 36 193ndash9

176 Luttrull JK Wan WL Kubak BM et al Treatment of ocular fungal

infections with oral fluconazole Am J Ophthalmol 1995 119 477ndash81

177 Akler ME Vellend H McNeely DM et al Use of fluconazole in the

treatment of candidal endophthalmitis Clin Infect Dis 1995 20 657ndash64

178 Christmas NJ Smiddy WE Vitrectomy and systemic fluconazole

for treatment of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1996 27 1012ndash18

179 EssmanTFFlynnHWSmiddyWEet al Treatment outcomes in a

10-year study of endogenous fungal endophthalmitis Ophthalmic Surg

Lasers 1997 28 185ndash94

180 Martinez-Vazquez C Fernandez-Ulloa J Bordon J et al Candida

albicans endophthalmitis in brown heroin addicts response to early vit-

rectomyprecededand followedbyantifungal therapyClin InfectDis1998

27 1130ndash3

181 Aleixo MJ Caldeira L Ferreira ML Candida albicans meningitis

clinical case J Infect 2000 40 191ndash2

182 InoueY YozuR Ueda T et al A case report ofCandida parapsilo-

sis endocarditis J Heart Valve Dis 1998 7 240ndash2

183 Isalska BJ Stanbridge TN Fluconazole in the treatment of candi-

dal prosthetic valve endocarditis BMJ 1988 297 178ndash9

184 Martino P Meloni G Cassone A Candidal endocarditis and treat-

ment with fluconazole and granulocyte-macrophage colony-stimulating

factor Ann Intern Med 1990 112 966ndash7

185 Roupie E Darmon JY Brochard L et al Fluconazole therapy of

candidal native valveendocarditisEur JClinMicrobiol InfectDis199110458ndash9

186 Hernandez JA Gonzalez-Moreno M Llibre JM et al Candidal

mitral endocarditis and long-term treatment with fluconazole in a patient

with human immunodeficiency virus infection Clin Infect Dis 1992 151062ndash3

187 Venditti MDeBernardis FMicozzi A et al Fluconazole treatment

of catheter-related right-sided endocarditis caused by Candida albicans

and associated with endophthalmitis and folliculitis Clin Infect Dis 1992

14 422ndash6

188 Wallbridge DR McCartney AC Richardson MD Fluconazole in

the treatment ofCandidaprosthetic valveendocarditisMycoses199336259ndash61

189 Otaki M Kitamura N Candida prosthetic valve endocarditis An

autopsy review Int Surg 1993 78 252ndash3

190 Czwerwiec FS Bilsker MS Kamerman ML et al Long-term sur-

vival after fluconazole therapy of candidal prosthetic valve endocarditis

Am J Med 1993 94 545ndash6

191 Thakur RK Skelcy KM Kahn RN et al Successful treatment of

Candida prosthetic valve endocarditis with a combination of fluconazole

and amphotericin B Crit Care Med 1994 22 712ndash14

192 Cancelas JA Lopez JCabezudoE et al Native valve endocarditis

due toCandida parapsilosis a late complication after bonemarrow trans-

plantation-related fungemia Bone Marrow Transplant 1994 13 333ndash4

193 Zahid MA Klotz SA Hinthorn DR Medical treatment of recurrent

candidemia in a patient with probable Candida parapsilosis prosthetic

valve endocarditis Chest 1994 105 1597ndash8

194 Wells CJ Leech G Lever AM et al Treatment of native valve

Candida endocarditis with fluconazole J Infect 1995 31 233ndash5

195 Gilbert HM Peters ED Lang SJ et al Successful treatment of

fungal prosthetic valve endocarditis case report and review Clin Infect

Dis 1996 22 348ndash54

196 Nguyen MH Nguyen ML Yu VL et al Candida prosthetic valve

endocarditis prospective study of six cases and review of the literature

Clin Infect Dis 1996 22 262ndash7

197 Lejko-Zupanc T Kozelj M A case of recurrent Candida parapsilo-

sis prosthetic valve endocarditis cure bymedical treatment alone J Infect

1997 35 81ndash2

198 Joly V BelmatougN Leperre A et al Pacemaker endocarditis due

to Candida albicans case report and review Clin Infect Dis 1997 251359ndash62

199 Rex JH Walsh T Sobel JD et al Practice guidelines for the treat-

mentof candidiasis InfectiousDiseasesSocietyofAmericaClin InfectDis

2000 30 662ndash78

200 Baddour LM Long-term suppressive therapy for Candida para-

psilosis-induced prosthetic valve endocarditis Mayo Clin Proc 1995

70 773ndash5

201 Melgar GR Nasser RM Gordon SM Fungal prosthetic valve

endocarditis in 16 patients An 11-year experience in a tertiary care hos-

pital Medicine 1997 76 94ndash103

202 Dupont H Paugam-Burtz C Muller-Serieys C et al Predictive

factors of mortality due to polymicrobial peritonitis with Candida isolation

in peritoneal fluid in critically ill patients Arch Surg 2002 137 1341ndash6

203 Lee SC FungCP ChenHY et alCandida peritonitis due to peptic

ulcer perforation incidence rate risk factors prognosis and susceptibility

to fluconazole and amphotericin B Diagn Microbiol Infect Dis 2002 4423ndash7

204 Levine J Bernard DB Idelson BA et al Fungal peritonitis compli-

cating continuous ambulatory peritoneal dialysis successful treatment

with fluconazole a new orally active antifungal agent Am J Med 1989

86 825ndash7

205 Michel C Courdavault L al Khayat R et al Fungal peritonitis in

patients on peritoneal dialysis Am J Nephrol 1994 14 113ndash20

206 WangAYYuAWLi PKet al Factors predicting outcomeof fungal

peritonitis in peritoneal dialysis analysis of a 9-year experience of fungal

peritonitis in a single center Am J Kidney Dis 2000 36 1183ndash92

207 Hawkins JL Baddour LM Candida lusitaniae infections in the era

of fluconazole availability Clin Infect Dis 2003 36 14ndash18

Review

409

208 KauffmanCAVazquezJASobel JDetal Prospectivemulticenter

surveillance study of funguria in hospitalized patients The National Insti-

tute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group

Clin Infect Dis 2000 30 14ndash18

209 Sobel JD Kauffman CA McKinsey D et al Candiduria a random-

ized double-blind study of treatment with fluconazole and placebo The

National Institute of Allergy and Infectious Diseases (NIAID) Mycoses

Study Group Clin Infect Dis 2000 30 19ndash24

210 LundstromTSobel JNosocomial candiduria a reviewClin Infect

Dis 2001 32 1602ndash7

211 Kaufman D Boyle R Hazen KC et al Fluconazole prophylaxis

against fungal colonization and infection in preterm infants N Engl J

Med 2001 345 1660ndash6

212 Kicklighter SD Springer SC Cox T et al Fluconazole for the pro-

phylaxis against candidal rectal colonization in the very low birth weight

infant Pediatrics 2001 107 293ndash8

213 McGuire W Clerihew L Austin N Prophylactic intravenous anti-

fungal agents to prevent mortality and morbidity in very low birth weight

infants Cochrane Database Syst Rev 2004 CD003850

214 Agarwal JBansalSMalikGKetal Trends inneonatal septicemia

emergence of non-albicans Candida Indian Pediatr 2004 41 712ndash15

215 FasanoCOrsquoKeefe JGibbsD Fluconazole treatment of neonates

and infants with severe fungal infections not treatable with conventional

agents Eur J Clin Microbiol Infect Dis 1994 13 351ndash4

216 Wainer S Cooper PA Gouws H et al Prospective study of flu-

conazole therapy in systemicneonatal fungal infectionPediatr InfectDis J

1997 16 763ndash7

217 Huang YC Lin TY Lien RI et al Fluconazole therapy in neonatal

candidemia Am J Perinatol 2000 17 411ndash15

218 Huttova M Hartmanova I Kralinsky K et al Candida fungemia in

neonates treated with fluconazole report of forty cases including eight

with meningitis Pediatr Infect Dis J 1998 17 1012ndash15

219 Gurpinar AN Balkan E Kilic N et al Fluconazole treatment of

neonates and infants with severe fungal infections J Int Med Res 1997

25 214ndash18

220 Driessen M Ellis JB Muwazi F et al The treatment of systemic

candidiasis in neonates with oral fluconazole Ann Trop Pediatr 1997 17263ndash71

221 Driessen M Ellis JB Cooper PA et al Fluconazole vs

amphotericin B for the treatment of neonatal fungal septicemia

a prospective randomized trial Pediatr Infect Dis J 1997 151107ndash12

222 Marr B Gross S Cunningham C et al Candidal sepsis and

meningitis in a very-low-birth-weight infant successfully treated with flu-

conazole and flucytosine Clin Infect Dis 1994 19 795ndash6

223 Oleinik EM Della-Latta P Rinaldi MG et al Candida lusitaniae

osteomyelitis in a premature infant Am J Perinatol 1993 10 313ndash15

224 Mondal RK Singhi SC Chakrabarti A Randomized comparison

between fluconazole and itraconazole for the treatment of candidemia in a

pediatric intensive care unit a preliminary study Pediatr Crit Care Med

2004 5 561ndash5

225 Viscoli C Castagnola E Fioredda F et al Fluconazole in the treat-

ment of candidiasis in immunocompromised children Antimicrob Agents

Chemother 1991 35 365ndash7

226 Decruyenaere J Colardyn F Vogelaers D et al Combined use of

fluconazole and selective digestive decontamination in the prevention of

fungal infection after adult liver transplantation Transplant Proc 1995 273515ndash16

227 Koh LP Kurup A Goh YT et al Randomized trial of fluconazole

versus low-dose amphotericin B in prophylaxis against fungal infections in

patients undergoing hematopoietic stem cell transplantationAmJHema-

tol 2002 71 260ndash7

228 Gluckman E Esperou-Bourdeau H Ribaud P et al Comparaison

entre le fluconazole et le ketoconazole pour la prophylaxie des infections

fongiques chez les patients traites par greffe de moelle allogenique Cah

Oncol 1993 2 167ndash9

Review

410

208 KauffmanCAVazquezJASobel JDetal Prospectivemulticenter

surveillance study of funguria in hospitalized patients The National Insti-

tute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group

Clin Infect Dis 2000 30 14ndash18

209 Sobel JD Kauffman CA McKinsey D et al Candiduria a random-

ized double-blind study of treatment with fluconazole and placebo The

National Institute of Allergy and Infectious Diseases (NIAID) Mycoses

Study Group Clin Infect Dis 2000 30 19ndash24

210 LundstromTSobel JNosocomial candiduria a reviewClin Infect

Dis 2001 32 1602ndash7

211 Kaufman D Boyle R Hazen KC et al Fluconazole prophylaxis

against fungal colonization and infection in preterm infants N Engl J

Med 2001 345 1660ndash6

212 Kicklighter SD Springer SC Cox T et al Fluconazole for the pro-

phylaxis against candidal rectal colonization in the very low birth weight

infant Pediatrics 2001 107 293ndash8

213 McGuire W Clerihew L Austin N Prophylactic intravenous anti-

fungal agents to prevent mortality and morbidity in very low birth weight

infants Cochrane Database Syst Rev 2004 CD003850

214 Agarwal JBansalSMalikGKetal Trends inneonatal septicemia

emergence of non-albicans Candida Indian Pediatr 2004 41 712ndash15

215 FasanoCOrsquoKeefe JGibbsD Fluconazole treatment of neonates

and infants with severe fungal infections not treatable with conventional

agents Eur J Clin Microbiol Infect Dis 1994 13 351ndash4

216 Wainer S Cooper PA Gouws H et al Prospective study of flu-

conazole therapy in systemicneonatal fungal infectionPediatr InfectDis J

1997 16 763ndash7

217 Huang YC Lin TY Lien RI et al Fluconazole therapy in neonatal

candidemia Am J Perinatol 2000 17 411ndash15

218 Huttova M Hartmanova I Kralinsky K et al Candida fungemia in

neonates treated with fluconazole report of forty cases including eight

with meningitis Pediatr Infect Dis J 1998 17 1012ndash15

219 Gurpinar AN Balkan E Kilic N et al Fluconazole treatment of

neonates and infants with severe fungal infections J Int Med Res 1997

25 214ndash18

220 Driessen M Ellis JB Muwazi F et al The treatment of systemic

candidiasis in neonates with oral fluconazole Ann Trop Pediatr 1997 17263ndash71

221 Driessen M Ellis JB Cooper PA et al Fluconazole vs

amphotericin B for the treatment of neonatal fungal septicemia

a prospective randomized trial Pediatr Infect Dis J 1997 151107ndash12

222 Marr B Gross S Cunningham C et al Candidal sepsis and

meningitis in a very-low-birth-weight infant successfully treated with flu-

conazole and flucytosine Clin Infect Dis 1994 19 795ndash6

223 Oleinik EM Della-Latta P Rinaldi MG et al Candida lusitaniae

osteomyelitis in a premature infant Am J Perinatol 1993 10 313ndash15

224 Mondal RK Singhi SC Chakrabarti A Randomized comparison

between fluconazole and itraconazole for the treatment of candidemia in a

pediatric intensive care unit a preliminary study Pediatr Crit Care Med

2004 5 561ndash5

225 Viscoli C Castagnola E Fioredda F et al Fluconazole in the treat-

ment of candidiasis in immunocompromised children Antimicrob Agents

Chemother 1991 35 365ndash7

226 Decruyenaere J Colardyn F Vogelaers D et al Combined use of

fluconazole and selective digestive decontamination in the prevention of

fungal infection after adult liver transplantation Transplant Proc 1995 273515ndash16

227 Koh LP Kurup A Goh YT et al Randomized trial of fluconazole

versus low-dose amphotericin B in prophylaxis against fungal infections in

patients undergoing hematopoietic stem cell transplantationAmJHema-

tol 2002 71 260ndash7

228 Gluckman E Esperou-Bourdeau H Ribaud P et al Comparaison

entre le fluconazole et le ketoconazole pour la prophylaxie des infections

fongiques chez les patients traites par greffe de moelle allogenique Cah

Oncol 1993 2 167ndash9

Review

410